Pyridone derivative, composition and use as antiviral drug thereof

ABSTRACT

The present disclosure belongs to the field of medicinal chemistry, and relates to a novel pyridone derivative represented by Formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, and use thereof in the preparation of a drug for preventing or treating diseases such as influenza type A viral infection and/or influenza type B viral infection, particularly use thereof as a PA subunit cap-dependent endonuclease inhibitor for preventing or treating diseases such as influenza type A viral infection and/or influenza type B viral infection. The compounds of the present disclosure have significant activity in inhibiting influenza endonuclease and influenza DNA, can be used either alone or in combination with a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor or other anti-influenza drugs, significantly shorten the time of influenza infection and reduces mortality, and have excellent clinical application prospects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is U.S. national phase under 35 U.S.C. § 371 ofInternational Patent Application No. PCT/CN2019/071902, filed on Jan.16, 2019, which claims priority to Chinese Application No.201810044308.4, filed on Jan. 17, 2018, and Chinese Application No.201811517425.4, filed on Dec. 12, 2018, the contents of all of which areincorporated by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present disclosure belongs to the field of medicinal chemistry, andspecifically relates to a novel pyridone derivative or a stereoisomer, apharmaceutically acceptable salt, a solvate or a crystal thereof, to apharmaceutical composition containing the foregoing pyridone derivativeor the stereoisomer, the pharmaceutically acceptable salt, the solvateor the crystal thereof, and to use thereof as an antiviral drug, inparticular, use thereof in the preparation of a drug as a cap-dependentendonuclease inhibitor for preventing and/or treating influenzainfection, in particular, such as use thereof in the preparation of adrug for preventing and/or treating influenza type A viral infectionand/or influenza type B viral infection.

BACKGROUND OF THE INVENTION

The influenza is an acute respiratory infection caused by an influenzavirus. Every year, influenza can cause thousands of deaths, andlarge-scale influenza outbreaks can cause millions of deaths worldwide.Although influenza vaccines and antiviral drugs such as amantadine canbe used to prevent and treat influenza, their prevention and efficacyare very limited, and it is required to develop a broader spectrum ofvaccine and more effective anti-influenza drug.

The neuraminidase inhibitors Oseltamivir and Zanamivir can suppressviral budding and release, but clinically the efficacy of neuraminidaseinhibitors in critically ill patients is doubtful, and the widespreadresistance is also a problem of neuraminidase inhibitors that must beconsidered. Due to the fear of a highly lethal new influenza pandemic, anew mechanism of anti-influenza drugs is urgently needed in the clinic.

The transcription of 8 RNA fragments is a critical step in the lifecourse of influenza viruses. RNA polymerase plays a key role in thisstep. RNA polymerase is a trimer composed of three subunits PA, PB1 andPB2, which is responsible for the replication and transcription of viralRNA in the nuclei of infected host cells. The transcription of influenzavirus RNA has a special “cap snatching” mechanism, the PB2 subunit isresponsible for recognizing and binding to the “cap structure” of thehost precursor mRNA, and the PA subunit cleaves the host mRNA as aprimer to initiate the transcription process. The cleaved mRNA primersare used in the PB1 subunit for the synthesis of viral mRNA. Because thecap-dependent endonuclease of the PA subunit is very conservative duringinfluenza variation and is necessary for viral life courses, and thebinding site is specific, the binding domain is well suited as a targetto develop new anti-influenza drugs. Since the endonuclease bindingsites of influenza type A and influenza type B are very similar,cap-dependent endonuclease inhibitors have activity against bothinfluenza type A and influenza type B viruses. The marketed influenzatreatment drug Baloxavir marboxil is a cap-dependent endonucleaseinhibitor that has a clinically highly effective therapeutic effect ontype A/B influenza. CN102803260A discloses a substituted polycycliccarbamoylpyridone derivative which has an inhibitory activity against acap-dependent endonuclease and can be used as a therapeutic and/orpreventive agent for influenza infectious diseases.

SUMMARY OF THE INVENTION

One of the purposes of the present disclosure is to provide a novelpyridone derivative which can be used as a cap-dependent endonucleaseinhibitor and which is superior to the exsiting pyridone derivatives inat least one aspect of activity, pharmacokinetic properties such asbioavailability and cytotoxicity.

A second purpose of the present disclosure is to provide a pyridonederivative which not only has excellent cap-dependent endonucleaseinhibitory activity and low cytotoxicity, but also has significantlyimproved pharmacokinetic properties, particularly bioavailability.

To achieve the above purposes, the present disclosure employs thefollowing technical solutions:

A pyridone derivative represented by Formula (I) or a stereoisomer, apharmaceutically acceptable salt, a solvate or a crystal thereof,

-   -   wherein:    -   (1) A is selected from N or CR₁, R₁ is selected from hydrogen,        cyano, hydroxy, halogen, carboxyl, ester, amide, sulfonyl amide;        or, R₁ is selected from the following unsubstituted or        substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆        hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, carbonyl hydrazide,        C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆        hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl, C₁₋₆        hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆        cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆        cycloalkylamino carbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆        cycloalkylamino carbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈        heterocycloalkoxy, C₄₋₈ heterocycloalkylamino, C₄₋₈        heterocycloalkyl sulfydryl, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈        heterocycloalkylamino carbonyl, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, C₆₋₁₀        aryloxy hydrocarbyl, C₆₋₁₀ arylamino, C₆₋₁₀ aryl sulfydryl,        C₆₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆ hydrocarbyl        sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkyl        sulfonylamino, C₆₋₁₀ aryl sulfonyl, C₆₋₁₀ aryl sulfonylamino,        aminooxalyl amino, aminooxalyl, C₆₋₁₀ arylamino carbonyl or        C₅₋₁₀ arylamino carbonylamino;    -   (2) M is selected from N or CR₂, R₂ is selected from hydrogen,        cyano, hydroxy, halogen, carboxyl, ester, amide, sulfonyl amide;        or, R₂ is selected from the following unsubstituted or        substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆        hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, carbonyl hydrazide,        C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆        hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl, C₁₋₆        hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆        cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆        cycloalkylamino carbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆        cycloalkylamino carbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈        heterocycloalkoxy, C₄₋₈ heterocycloalkylamino, C₄₋₈        heterocycloalkyl sulfydryl, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈        heterocycloalkylamino carbonyl, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, C₅₋₁₀        aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀ aryl sulfydryl,        C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆ hydrocarbyl        sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkyl        sulfonylamino, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ aryl sulfonylamino,        aminooxalyl amino, aminooxalyl, C₅₋₁₀ arylamino carbonyl or        C₅₋₁₀ arylamino carbonylamino; or, R₁ and R₂ are connected and        form a first ring together with carbon atoms connected        therewith, or R₂ and R₇ are connected and form a second ring        together with carbon atoms connected therewith;    -   (3) Q is selected from N or CR₃, R₃ is selected from hydrogen,        cyano, carboxyl, ester, amide; or, R₃ is selected from the        following unsubstituted or substituted groups: C₁₋₆ hydrocarbyl,        C₃₋₆ cycloalkyl, C₄₋₈ heterocycloalkyl, C₅₋₁₀ aryl, C₃₋₆        cycloalkyl sulfydryl, spirocyclic ring, bridged cyclic ring,        C₃₋₆ cycloalkyl sulfydryl C₁₋₆ hydrocarbyl, C₃₋₆ cycloalkyl C₁₋₆        hydrocarbyl sulfydryl C₁₋₆ hydrocarbyl, C₃₋₆ cycloalkyl C₁₋₆        hydrocarbyl sulfydryl cycloalkyl, C₃₋₆ cycloalkyloxy cycloalkyl,        cycloamide C₁₋₆ hydrocarbyl, cycloamide cycloalkyl,        cyclosulfonyl C₁₋₆ hydrocarbyl, cyclosulfonyl cycloalkyl; or, R₃        and R₄ are connected and form a third ring together with carbon        atoms connected therewith;    -   (4) R is selected from NH, carbonyl or CR₄R₅, R₄ and R₅ are        independently selected from hydrogen, cyano, carboxyl, ester,        amide; or, R₄ and R₅ are independently selected from the        following unsubstituted or substituted groups: C₁₋₆ hydrocarbyl,        C₁₋₆ hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆        hydrocarbylsulfydryl, C₁₋₆ hydrocarbylcarbonyl, C₁₋₆        hydrocarbylamino carbonyl, C₁₋₆ hydrocarbylcarbonyl amino, C₁₋₆        hydrocarbyloxy carbonyl, C₁₋₆ hydrocarbylamino acylamino, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆        cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆        cycloalkylamino carbonyl, C₃₋₆ cycloalkylamino carbonylamino,        C₃₋₆ cycloalkylcarbonyl amino, C₄₋₈ heterocycloalkyl, C₄₋₈        heterocycloalkoxy, C₄₋₈ heterocycloalkylamino, C₄₋₈        heterocycloalkyl sulfydryl, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈        heterocycloalkylamino carbonyl, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, C₅₋₁₀        aryloxy C₁₋₆ hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀ aryl sulfydryl,        C₅₋₁₀ aryl carbonyl, C₅₋₁₀ arylamino carbonyl or C₅₋₁₀ arylamino        carbonylamino; or, R₄ and R₅ are connected and form a fourth        ring together with carbon atoms connected therewith;    -   (5) R₆ is selected from hydrogen or the following unsubstituted        or substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy,        C₁₋₆ hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, carbonyl        hydrazide, C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino        carbonyl, C₁₋₆ hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy        carbonyl, C₁₋₆ hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino        carbonylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆        cycloalkylamino, C₃₋₆ cycloalkylsulfydryl, C₃₋₆        cycloalkylcarbonyl, C₃₋₆ cycloalkylamino carbonyl, C₃₋₆        cycloalkylcarbonyl amino, C₃₋₆ cycloalkylamino carbonylamino,        C₄₋₈ heterocycloalkyl, C₄₋₈ heterocycloalkoxy, C₄₋₈        heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈        heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylamino carbonyl,        C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, C₅₋₁₀ aryloxy hydrocarbyl, C₅₋₁₀        arylamino, C₅₋₁₀ aryl sulfydryl, C₅₋₁₀ aryl carbonyl, C₁₋₆        hydrocarbyl sulfonyl, C₁₋₆ hydrocarbyl sulfonylamino, C₃₋₆        cycloalkyl sulfonyl, C₃₋₆ cycloalkyl sulfonylamino, C₅₋₁₀ aryl        sulfonyl, C₅₋₁₀ aryl sulfonylamino, aminooxalyl amino,        aminooxalyl, C₅₋₁₀ arylamino carbonyl or C₅₋₁₀ arylamino        carbonylamino; or, R₆ is a fifth ring; or, R₆ and R are        connected and form a sixth ring together with a nitrogen atom        both connected therewith, and the sixth ring is monocyclic,        spiro, fused cyclic, bridged cyclic or polycyclic, and        optionally contains 1, 2, 3 or more groups independently        selected from heteroatom, C═O, S═O or SO₂, in addition to the        nitrogen atom which R and R₆ are both connected with;    -   (6) m is 0, 1, 2, 3, 4 or 5, and R₇ is selected from hydrogen,        hydroxy, cyano, halogen, carboxyl, ester, sulfonyl amide, amide;        or, R₇ is selected from the following unsubstituted or        substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆        hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, carbonyl hydrazide,        C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆        hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl, C₁₋₆        hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆        cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆        cycloalkylamino carbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆        cycloalkylamino carbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈        heterocycloalkoxy, C₄₋₈ heterocycloalkylamino, C₄₋₈        heterocycloalkyl sulfydryl, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈        heterocycloalkylamino carbonyl, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, C₅₋₁₀        aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀ aryl sulfydryl,        C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆        hydrocarbylsulfonyl amide, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆        cycloalkylsulfonyl amide, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀        arylsulfonyl amide, aminooxalyl amino, aminooxalyl, C₅₋₁₀        arylamino carbonyl or C₅₋₁₀ arylamino carbonylamino; or, m is 2,        3, 4 or 5, and one or more pairs of neighboring R₇ are connected        and form a seventhring together with carbon atoms connected        therewith; or, R₂ and R₇ are connected and form the second ring        together with carbon atoms connected therewith;    -   (7) X is selected from Y(CH₂)_(n), —CH(OCH₃), —CH(SCH₃), N, O or        S, Y is a single bond, NH, 0 or S, and n is 0, 1, 2 or 3;    -   (8) W is hydrogen or a group that is metabolized to a parent        drug by chemical means and/or by the action of an enzyme in        vivo;    -   (9) Ar1 and Ar2 are independently selected from a phenyl ring,        or a heteroaromatic ring containing 1, 2, 3 or more heteroatoms;    -   (10) the first ring, the second ring, the third ring, the fourth        ring, the fifth ring, and the seventh ring are independently an        unsubstituted or substituted carbocyclic ring uninterrupted or        interrupted by 1, 2, 3 or more selected from heteroatom, C═O,        S═O or SO₂, and the first ring, the second ring, the third ring,        the fourth ring, the fifth ring, and the seventh ring are        independently monocyclic, spiro, fused cyclic, bridged cyclic or        polycyclic.

According to the present disclosure, when there are a plurality of R₇(that is, m is greater than 1), whether R₇ is the same or different isno particular required.

According to a specific aspect of the present disclosure, Ar1 and Ar2are both a phenyl ring and the pyridone derivative is represented byFormula (II):

According to another aspect of the present disclosure, at least one ofAr1 and Ar2 is a heteroaromatic ring.

According to the present disclosure, in the heterocyclic ring or theheteroaromatic ring, a heteroatom is dependently selected from N, O, orS.

According to some embodiments of the present disclosure, A is CR₁, M isCR₂, and R₁ and R₂ are connected and form the first ring together withcarbon atoms connected therewith.

According to some embodiments of the present disclosure, Q is CR₃, R isCR₄R₅, and R₃ and R₄ are connected and form the second ring togetherwith carbon atoms connected therewith.

According to certain embodiments of the present disclosure, R is CR₄R₅,and R₄ and R₆ are connected and form the sixth ring together withnitrogen and carbon atoms connected therewith.

According to further embodiments of the present disclosure, W in Formula(I) comprises, but not limited to,

-   -   (a) —C(═O)—R₈; (b) —C(═O)—(CH₂)_(k)—R₈, k is selected from        0-3; (c) —C(═O)—O—(CH₂)_(k)—R₈, k is selected from 0-3; (d)        —CH₂—O—R₈; (e) —CH₂—O—C(═O)—R₈; (f) —CH₂—O—C(═O)—O—R₈; (g)        —CH(—CH₃)—O—C(═O)—R₈; (h) —CH(—CH₃)—O—C(C═O)—O—(CH₂)_(k)—R₈, k        is selected from 0-3; (i) —CH₂—O—P(═O)(OH)₂; (j)        —CH₂—O—P(═O)(OPh)(NHR₈); (k) —CH₂—O—P(═O)(OCH₂OC(═O)OR₈)₂; R₈ is        selected from the following unsubstituted or substituted groups:        C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆ hydrocarbylamino,        C₁₋₆ hydrocarbylsulfydryl, carbonyl hydrazide, C₁₋₆ hydrocarbyl        carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆        hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl, C₁₋₆        hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆        cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆        cycloalkylamino carbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆        cycloalkylamino carbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈        heterocycloalkoxy, C₄₋₈ heterocycloalkylamino, C₄₋₈        heterocycloalkyl sulfydryl, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈        heterocycloalkylamino carbonyl, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy, C₅₋₁₀        aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀ aryl sulfydryl,        C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆ hydrocarbyl        sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkyl        sulfonylamino, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ aryl sulfonylamino,        aminooxalyl amino, aminooxalyl, C₅₋₁₀ arylamino carbonyl or        C₅₋₁₀ arylamino carbonylamino.

According to a preferable aspect of the present disclosure, when thesixth ring is a spiro ring, a common carbon atom of the spiro ring and anitrogen atom shared by the spiro ring and a parent ring (the parentring refers to a ring present in general formula (I), similarlyhereinafter) are adjacent or spaced by one atom.

According to another specific embodiment of the present disclosure, whenthe sixth ring is a spiro ring, a ring in the spiro ring that shares thenitrogen atom with a parent ring has an oxygen atom or a nitrogen atomat a position opposite to the shared nitrogen atom.

According to another preferable aspect of the present disclosure, whenthe sixth ring is a spiro ring, a ring in the spiro ring that shares thenitrogen atom with a parent ring is a 5-membered, 6-membered, 7-memberedor 8-membered ring, and another ring is a 3-membered, 4-membered,5-membered or 6-membered carboatomic, oxygen-containing heterocyclic orsulfur-containing heterocyclic ring unsubstituted or substituted by asubstituent selected from halogen, C₁₋₃ hydrocarbyl or C₁₋₃halohydrocarbyl.

Further preferably, when the another ring has a substituent, thesubstituent is selected from methyl, fluoro, chloro, bromo,monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl,methoxymethyl, methoxyethyl, chloromethyl.

According to some specific and preferable aspect of the presentdisclosure, in Formula (I), the sixth ring formed by connecting R₆ and Rtogether with the nitrogen atom connected therewith is selected from thefollowing groups:

According to a preferable embodiment of the present disclosure, thepyridone derivative is represented by Formula IIa or Formula IIb:

-   -   in Formula IIa and Formula IIb,    -   G is O or CH₂;    -   Z is selected from CH₂, O or S;    -   p and q are respectively 0, 1 or 2, and the two are not 0 at the        same time, and when Z is O or S, p+q is greater than or equal to        2;    -   definitions of W, R₇ and m are respectively the same as        previous.

Further preferably, in Formula IIa and Formula IIb, p+q=1 or 2 or 3, andZ is CH₂; or, p=1 or 2, q=1 or 2, and Z is O or S.

According to some more specific embodiments of the present disclosure,R₇ is selected from hydrogen, hydroxy, cyano, halogen, C₁₋₆ hydrocarbyl,C₁₋₆ halohydrocarbyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy C₁₋₆ hydrocarbyl,hydroxy C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy.

Further preferably, in Formula IIa and Formula IIb, R₇ is connected to aphenyl ring.

Preferably, m is 1 or 2 or 3. In a specific embodiment, m is 1 or 2, andR₇ is selected from fluoro, chloro, bromo, methyl or trifluoromethyl,etc.

Preferably, W is selected from the following groups:

-   -   (a) —C(═O)—R₈; (b) —C(═O)—(CH₂)_(k)—R₈, k is selected from        0-3; (c) —C(═O)—O—(CH₂)_(k)—R₈, k is selected from 0-3; (e)        —CH₂—O—C(═O)—R₈; (f) —CH₂—O—C(═O)—O—R₈; (g)        —CH(—CH₃)—O—C(═O)—R₈; (h) —CH(—CH₃)—O—C(C═O)—O—(CH₂)_(k)—R₈, k        is selected from 0-3; (i) —CH₂—O—P(═O)(OH)₂; (j)        —CH₂—O—P(═O)(OPh)(NHR₈); (k) —CH₂—O—P(═O)(OCH₂OC(═O)OR₈)₂; R₈ is        selected from methyl, ethyl, isopropyl, or butyl.

In a specific embodiment, in Formula IIa and Formula IIb, W is (f)—CH₂—O—C(═O)—O—R₈, and R₈ is methyl, ethyl, isopropyl or butyl.

The pyridone derivatives represented by the above Formula IIa or FormulaIIb show the best activity, and the metabolic stability of the drug isremarkably improved, and it is expected to have positive effects on thephase II metabolism glucuronidation.

According to another aspect of the present disclosure, the pyridonederivative is represented by following Formula IIc:

-   -   in Formula IIc, a, b, c and d are respectively 0, 1, 2 or 3, and        a and b are not 0 or 3 at the same time, and c and d are not 0        or 3 at the same time;    -   E is CH₂ or 0;    -   K is CH₂ or 0;    -   definitions of W, R₇ and m are respectively the same as        previous.

Preferably, in Formula IIc, a+b=1 or 2 or 3, and c+d=1 or 2 or 3.

Preferably, in Formula IIc, R₇ is selected from hydrogen, hydroxy,cyano, halogen, C₁₋₆ hydrocarbyl, C₁₋₆ halohydrocarbyl, C₁₋₆ alkoxy C₁₋₆hydrocarbyl, hydroxy C₁₋₆ hydrocarbyl, C₁-6 hydrocarbyloxy.

More specifically, in Formula IIc, R₇ may be, for example, protium,deuterium, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl,methoxymethyl, etc.

Preferably, R₇ is connected to a phenyl ring.

Preferably, in Formula IIc, m is 0, 1, 2 or 3.

The compounds represented by Formula IIc, have a novel structure, andare highly active compounds against influenza type A and type B viruses.

According to an aspect of the present disclosure, when the fifth ring isa bridged ring, the bridged ring is bicyclic or tricyclic, and abridgehead carbon atom or a non-bridgehead carbon atom of the bridgedring is connected to a corresponding nitrogen atom on a parent ring.

According to some specific implementations of the present disclosure,when the fifth ring is a bridged ring, the bridged ring is selected frombicyclo[1.1.1]pentane, bicyclo[2.1.0]pentane, bicyclo[2.1.1]hexane,bicyclo[2.2.0]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.0]heptane,bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.0] octane.

Further, when the fifth ring is a bridged ring, the bridged ring isunsubstituted or substituted by 1, 2, 3 or more substituents selectedfrom fluoro, chloro, bromo, trifluoromethyl, —CH₂OH or —CH₂OCH₂.

According to another aspect of the present disclosure, the pyridonederivative is represented by following Formula IId or Formula IIe:

-   -   in Formula IId and Formula IIe,    -   R₁₂ is selected from hydrogen, hydroxy, cyano, halogen, C₁₋₆        hydrocarbyl, C₁₋₆ halohydrocarbyl, C₁₋₆ alkoxy C₁₋₆ hydrocarbyl,        C₁₋₆ hydroxyl-substituted hydrocarbyl, C₁₋₆ hydrocarbyloxy;    -   definitions of W, R₇ and m are respectively the same as        previous.

Preferably, R₁₂ is selected from hydrogen, fluoro, chloro, methyl,ethyl, isopropyl, trifluoromethyl, methoxymethyl or hydroxymethyl, etc.

Preferably, in Formula IId or IIe, R₇ is selected from hydrogen,hydroxy, cyano, halogen, C₁₋₆ hydrocarbyl, C₁₋₆ halohydrocarbyl, C₁₋₆alkoxy C₁₋₆ hydrocarbyl, hydroxy C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy.Preferably, R₇ is connected to a phenyl ring.

Compounds represented by Formula IId and Formula IIe are significantlyoptimized in space volume and spatial configuration of the groupscompared to existing compounds, and thus have potent inhibition ofinfluenza A activity, have a significant metabolic advantage (Metabolicstability), and have good development prospects.

According to one aspect of the present disclosure, when the sixth ringformed by R₆ and R and the nitrogen atom connected therewith is a4-membered, 5-membered, 6-membered or 7-membered monocyclic ring,Formula (I) further meets at least one of the following conditions:

-   -   i) in addition to the nitrogen atom to which both R and R₆ are        connected, the sixth ring optionally contains one or two of        oxygen atom, another nitrogen atom, C═O, S═O and SO₂;    -   ii) the sixth ring has at least one substituent selected from        hydroxy, cyano, carboxyl, ester, sulfonyl amide, amide, C₂₋₆        alkenyl, C₃₋₆ cycloalkyl, C₃₋₆ halocycloalkyl, C₃₋₆ cycloalkoxy,        C₁₋₆ hydrocarbyloxy C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy C₁₋₆        hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆        hydrocarbylsulfydryl, carbonyl hydrazide, C₁₋₆ hydrocarbyl        carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆        hydrocarbylcarbonyl amino or C₁₋₆ hydrocarbyloxy carbonyl;    -   iii) the sixth ring has an intra carbon-carbon ethylenic bond,        or the sixth ring has an exocyclic carbon-carbon ethylenic bond        sharing one carbon atom with the sixth ring;    -   iv) at least one of Ar1 and Ar2 is a nitrogen-containing        heteroaromatic ring;    -   v) at least one of A and M is N.

Further, in the condition ii), the substituent in the sixth ring isselected from OCH₂CH₂OCH₃, —CH₂OCHF₂, —CH₂OCF₃, —CH₂OH, —OH, —COOH,—COOCH₃, —CONH₂, —OCH₂F, —OCHF₂, —OCF₃, —CH₂OCH₃,

According to a specific aspect of the present disclosure, when the sixthring is a 4-membered, 5-membered, 6-membered or 7-membered monocyclicring, the sixth ring contains a total of 2 heteroatoms and the 2heteroatoms are in para or meta positions, and one of the heteroatoms isa nitrogen atom connected to both R and R₆, and the other heteroatom isoxygen or nitrogen. The representative sixth ring is, for example:

According to a more specific aspect of the present disclosure, the twoheteroatoms contained in the sixth ring are all nitrogen atoms and thetwo nitrogen atoms are in opposite positions, while the sixth ringfurther has a C═O. The representative sixth ring is, for example:

According to another specific aspect of the present disclosure, when thesixth ring is a 4-membered, 5-membered, 6-membered or 7-memberedmonocyclic ring, the sixth ring contains a total of 1 heteroatoms whichis the nitrogen atom connected to both R and R₆ (that is, the nitrogenshared by the parent ring), while the sixth ring has an intracarbon-carbon ethylenic bond or an exocyclic carbon-carbon ethylenicbond. The representative sixth ring is, for example:

According to an aspect of the present disclosure, in Formula (I), thesixth ring is an unsubstituted morpholine ring, and further meets atleast one of the following conditions:

-   -   i) one of A and M is N, and the other is correspondingly CR₁ or        CR₂, while Q is CH;    -   ii) at least one of Ar1 and Art is a nitrogen-containing        heteroaromatic ring containing 1 or 2 nitrogen atoms.

According to another aspect of the present disclosure, when the sixthring is a fused ring, the fused ring is a bicyclic ring, and one ringsharing a nitrogen atom with the parent ring is a saturated 5-memberedor 6-membered ring and optionally contains one or two groups selectedfrom O, another N, C═O, S═O, or SO₂, and the other ring is a 3-membered,4-membered, 5-membered or 6-membered saturated or unsaturated ring andoptionally contains one or two groups selected from O, N, C═O, S═O orSO₂.

According to another aspect of the present disclosure, when the sixthring is a fused ring, one ring of the fused ring sharing the N atom withthe parent ring is a piperidine or piperazine ring, and the other ringis a 5-membered or 6-membered heteroaromatic ring or a saturatedheterocyclic ring. Further, the 5-membered or 6-membered heteroaromaticring or the saturated heterocyclic ring is unsubstituted or substitutedby 1, 2, 3 or more substituents selected from hydroxy, cyano, carboxyl,ester, sulfonyl amide, amide, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆halohydrocarbyl, C₁₋₃ alkoxy, C₃₋₆ cyclohydrocarbyloxy, C₁₋₆hydrocarbyloxy C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbylamino, C₁₋₆hydrocarbylsulfydryl, carbonyl hydrazide, C₁₋₆ hydrocarbyl carbonyl,C₁₋₆ hydrocarbyl sulfonyl amide, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆hydrocarbylcarbonyl amino or C₁₋₆ hydrocarbyloxy carbonyl.

According to some specific embodiments of the present disclosure, thesixth ring is selected from the following groups:

According to some embodiments of the present disclosure, the sixth ringis a piperidine ring or a morpholine ring, a substituent in the ring ispreferably selected from, but not limited to, the following groups:alkoxyalkyl, haloalkoxyalkyl, hydroxyalkyl, ester, carboxyl, amide,cyano, cycloalkyl, cycloalkoxy, halocycloalkyl, hydroxy, hydroxy andalkyl/haloalkyl are connected to the same carbon atom, or cycloalkyl andhydroxyl are connected to the same carbon atom. The piperidine ring orthe morpholine ring is preferably selected from the following groups:

According to some embodiments of the present disclosure, the sixth ringis a piperidine heterocyclic ring (including an aromatic heterocyclicring or a saturated heterocyclic ring) or a piperazine heterocyclic ring(including an aromatic heterocyclic ring or a saturated heterocyclicring), and the substituent on the ring is preferably selected from, butnot limited to, the following groups: alkyl, alkoxy, haloalkyl, hydroxylor methanesulfonylamide. The piperidine heterocyclic ring (including anaromatic heterocyclic ring or a saturated heterocyclic ring) or thepiperazine heterocyclic ring is preferably selected from the followinggroups:

According to some embodiments of the present disclosure, the sixth ringis a piperazine ring, and the ring contains an oxo group (carbonyl), andsuch piperazine ring is preferably selected from, but not limited to:

According to some embodiments of the present disclosure, the sixth ringis an unsaturated piperidine ring, and the unsaturated bond is cyclic orexocyclic, and such unsaturated piperidine ring is preferably selectedfrom, but not limited to:

According to some preferable embodiments of the present disclosure, R₆is selected from:

According to some embodiments of the present disclosure, the sixth ringis a morpholine ring, and the compounds of Formula (I) specificallyrefer to the following four compounds:

According to the present disclosure, the pyridone derivative ispreferably selected from the following compounds:

The present disclosure further provides a pharmaceutical compositioncomprising the pyridone derivative represented by Formula (I) or astereoisomer, a pharmaceutically acceptable salt, a solvate or a crystalthereof.

Further, the pharmaceutical composition is an antiviral pharmaceuticalcomposition further optionally comprising one or more therapeutic agentsselected from the group consisting of a neuraminidase inhibitor, anucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor orother anti-influenza drugs.

Preferably, the antiviral pharmaceutical composition comprises at leastone therapeutic agent.

The present disclosure further relates to use of the pyridone derivativerepresented by Formula (I) or the stereoisomer, the pharmaceuticallyacceptable salt, the solvate, the crystal or a combination thereof inthe preparation of a drug for preventing and/or treating a viralinfection disease, the viral infection disease is preferably infectiousdiseases caused by influenza type A viruses and/or influenza type Bviruses.

The present disclosure further relates to use of the pyridone derivativerepresented by Formula (I) or the stereoisomer, the pharmaceuticallyacceptable salt, the solvate, the crystal or a combination thereof inthe preparation of an antiviral drug, the antiviral drug is preferably adrug or an agent inhibiting influenza cap-dependent endonucleaseactivities.

In the present disclosure, for convenience of description, in someplaces, the pyridone derivative represented by Formula (I) or thestereoisomer, the pharmaceutically acceptable salt, the solvate, thecrystal or any combination thereof is collectively referred to as thecompound of the present disclosure.

In the pharmaceutical composition according to the present disclosure,the compound of the present disclosure is preferably present in atherapeutically effective amount.

The above pharmaceutical composition usually comprises apharmaceutically acceptable carrier such as a pharmaceuticallyacceptable diluent, an excipient, a filler, a binder, a disintegrant, anabsorption enhancer, a surfactant, a lubricant, a fragrance, asweetener, etc.

Further, the pharmaceutical composition may employ any kind of dosageform, which may specifically be a tablet, a powder, a capsule, agranule, an oral liquid, an injection, a powder, a suppository, a pill,a cream, a paste, a gel, a pulvis, an inhalant, a suspension, a drysuspension, a patch, a lotion, a nano preparation, etc. The dosage formof the pharmaceutical composition is preferably a tablet, a capsule oran injection.

The above mentioned dosage forms of the drug can be prepared byconventional methods in the pharmaceutical field.

In a specific embodiment, the pharmaceutical composition according tothe present disclosure may be constituted by, for example, the followingratio (mass ratio):

compound of the present disclosure 5-95% lactose 1-60% starch 0-20%microcrystalline cellulose 1-40% carboxymethyl starch sodium  1-5%polyethylene glycol (PEG6000) 0-10% magnesium stearate  1-5%

The present disclosure further provides a process for the pyridonederivative, i.e., a compound of Formula (I) according to the presentdisclosure, which employs the following route:

According to a specific embodiment of the present disclosure, the abovereaction can be implemented according to the following steps:

Step-1: A and B are dissolved in ethyl acetate solution of 50% T₃P andreact at 60-100° C. for 1-10 hours to give Intermediate C.

Step-2: intermediate C and lithium chloride are reacted in DMA solutionat 100° C. for 12 hours, and the mixture is purified to give Compound D.

Step-3: the obtained Compound D and acyl chloride or halide are reactedin the presence of an alkali to give a hydroxy-protected Prodrug (I),wherein the alkali comprises an organic alkali and an inorganic alkali,and the organic alkali is selected from triethylamine, DIPEA, DBU, andpyridine, etc.; and the inorganic alkali is selected from sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride, potassium hydride, sodiumbicarbonate, etc.

Due to the implementations of the above technical solutions, the presentdisclosure has the following advantages over the prior art:

the present disclosure provides a novel pyridone derivative, which hasstrong inhibitory activity against influenza virus A and influenza virusB, and can be used alone for clinical treatment or in combination withother anti-influenza drugs such as neuraminidase inhibitors, nucleosidedrugs and PB2 inhibitors, and may rapidly cure influenza patients in theclinic. These compounds are superior to the exsiting pyridonederivatives in at least one aspect of activity, pharmacokineticproperties (such as bioavailability) and cytotoxicity.

Definition of Terms

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

The term “unsubstituted”, when used to define a group, means that thedefined group is not replaced by a group other than a hydrogen atom, inwhich case the group has the same meaning generally understood by one ofordinary skill in the art to which the present disclosure belongs. Forexample, an unsubstituted C₁₋₆ alkyl is a group generally understood bythose skilled in the art such as methyl, ethyl or the like.

The term “substituted”, when used to define a group, means that 1, 2, 3or more hydrogen atoms on the defined group are replaced by asubstituent, and the meaning of this group should be understood inconjunction with the substituent. In the present disclosure, unlessotherwise specified, when referring to “substituted”, it is meant thathydrogen atoms in a group defined thereby are replaced by 1, 2, 3 ormore substituents selected from the group consisting of:

cyano, halogen, hydroxy, carboxyl, ester, sulfonyl, sulphonyl amide,amide, carbonyl (—C(═O)—), C₁₋₆ hydrocarbyl S(═O)(═NH)—, amino, carbonylhydrazide, C₁₋₆ hydrocarbyl, halogenated C₁₋₆ hydrocarbyl,hydroxyl-substituted C₁₋₆ hydrocarbyl, acylamino-substituted C₁₋₆hydrocarbyl, C₁₋₆ hydrocarbyloxy, halogenated C₁₋₆ hydrocarbyloxy, C₁₋₆hydrocarbyloxy C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy C₁₋₆hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, C₁₋₆hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆ hydrocarbylamide, halogenated C₁₋₆ hydrocarbyl amide, C₁₋₆ hydrocarbyloxy acyl,C₁₋₆ hydrocarbylamino acylamino, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆hydrocarbyl sulphonyl amide, C₃₋₆ cycloalkyl, halogenated C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, halogenated C₃₋₆ cycloalkoxy, C₃₋₆cycloalkyl C₁₋₆ hydrocarbyl, C₃₋₆ cycloalkoxy C₁₋₆ hydrocarbyl, C₃₋₆cycloalkyl C₁₋₆ hydrocarbyloxy, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbyloxy C₁₋₆hydrocarbyloxy, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl C₁₋₆hydrocarbylamino, C₃₋₆ cycloalkylsulfydryl, halogenated C₃₋₆cycloalkylsulfydryl, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbylsulfydryl, C₃₋₆cycloalkyl sulfonyl, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbylsulfonyl, C₃₋₆cycloalkyl sulphonyl amide, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbyl sulphonylamide, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ cycloalkyl C₁₋₆hydrocarbylcarbonyl, C₃₋₆ cycloalkylamino carbonyl, C₃₋₆ cycloalkyl C₁₋₆hydrocarbylamino carbonyl, C₃₋₆ cycloalkyl amide, C₃₋₆ cycloalkyl C₁₋₆hydrocarbyl amide, C₃₋₆ cycloalkylamino amide, C₄₋₈ heterocycloalkyl,C₄₋₈ heterocycloalkoxy, halogenated C₄₋₈ heterocycloalkoxy, C₄₋₈heterocycloalkoxy C₁₋₆ hydrocarbyl, halogenated C₄₋₈ heterocycloalkoxyC₁₋₆ hydrocarbyl, C₄₋₈ heterocycloalkyl C₁₋₆ hydrocarbyloxy, halogenatedC₄₋₈ heterocycloalkyl C₁₋₆ hydrocarbyloxy, C₄₋₈ heterocycloalkyl C₁₋₆hydrocarbyl, C₄₋₈ heterocycloalkyl C₁₋₆ hydrocarbyloxy C₁₋₆ hydrocarbyl,C₄₋₈ heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈heterocycloalkyl C₁₋₆ hydrocarbyl sulfydryl, C₄₋₈ heterocycloalkylsulfonyl, C₄₋₈ heterocycloalkyl C₁₋₆ hydrocarbylsulfonyl, C₄₋₈heterocycloalkyl sulfonyl amide, C₄₋₈ heterocycloalkyl C₁₋₆ hydrocarbylsulfonyl amide, C₄₋₈ heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylC₁₋₆ hydrocarbyl carbonyl, carbonyl-substituted C₄₋₈ heterocycloalkyl,C₄₋₈ heterocycloalkylamino carbonyl, C₄₋₈ heterocycloalkyl amide, C₄₋₈heterocycloalkyl C₁₋₆ hydrocarbyl amide, C₅₋₁₀ aryl, C₅₋₁₀ aryloxy,C₅₋₁₀ aryloxy C₁₋₆ hydrocarbyl, C₅₋₁₀ aryl C₁₋₆ hydrocarbyl, C₅₋₁₀ arylC₁₋₆ hydrocarbyloxy, C₅₋₁₀ arylamino, C₅₋₁₀ aryl sulfydryl, C₅₋₁₀ arylC₁₋₆ hydrocarbyl sulfydryl, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ aryl C₁₋₆hydrocarbyl sulfonyl, C₅₋₁₀ aryl sulfonyl amide, C₅₋₁₀ aryl C₁₋₆hydrocarbyl sulfonyl amide, C₅₋₁₀ aryl carbonyl, C₅₋₁₀ aryl C₁₋₆hydrocarbyl carbonyl, C₅₋₁₀ arylamino carbonyl, C₅₋₁₀ aryl amide orC₅₋₁₀ arylamino amide.

Preferably, the above substituent is selected from cyano, halogen(preferably F, Cl, Br), hydroxy, carboxyl, ester, sulfonyl,sulphonylamino, carbonylamino, carbonyl, C₁₋₆ hydrocarbyl sulfinylamino,amino, carbonyl hydrazide, C₁₋₆ hydrocarbyl, halogenated C₁₋₆hydrocarbyl, hydroxyl-substituted C₁₋₆ hydrocarbyl, amide-substitutedC₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, halogenated C₁₋₆ hydrocarbyloxy,C₁₋₆ hydrocarbyloxy C₁₋₆ hydrocarbyl or C₁₋₆ hydrocarbyloxy C₁₋₆hydrocarbyloxy.

Further preferably, the above substituent is selected from cyano, F, Cl,Br, hydroxy, carboxyl, ester, sulfonyl, sulphonylamino, amide, carbonyl,methylsulfinylamino, ethylsulfinylamino, isopropylsulfinylamino,tert-butylsulfinylamino, amino, acylhydrazino, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl,n-pentyl, isopentyl, neopentyl, cyclohexyl, halomethyl (specifically,for example, trifluoromethyl), haloethyl, halo-n-propyl, halo-isopropyl,halocyclopropyl, halo-n-butyl, halo-isobutyl, halo-tert-butyl,halocyclobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl,hydroxyisopropyl, hydroxycyclopropyl, hydroxy-n-butyl, hydroxyisobutyl,hydroxy-tert-butyl, hydroxycyclobutyl, hydroxy-n-pentyl,hydroxyisopentyl, hydroxy neopentyl, hydroxycyclohexyl, methoxy, ethoxy,propoxy.

The substituent is usually placed before the group be substituted whencome to specific naming, for example, “C₁₋₃ alkoxy C₃₋₈ cycloalkyl C₁₋₆alkyl” means C₁₋₆ alkyl is substituted by C₃₋₈ cycloalkyl, and C₃₋₈cycloalkyl is further substituted by C₁₋₃ alkoxy, for example: thestructural formula of methoxycyclobutylmethyl is:

The term “uninterrupted”, when used to define a group, means that acovalent bond of the defined group is not interrupted by another group,in which case the group has the same meaning generally understood by oneof ordinary skill in the art to which the present disclosure belongs.For example, an unsubstituted cycloalkyl is a group generally understoodby those skilled in the art such as cyclobutyl, cyclopentyl or the like.

The term “interrupt” or “interrupted”, when used to define a group,means that one or more covalent bonds of the defined group areinterrupted by interrupting atoms or groups, and the meaning of thisgroup should be understood in conjunction with the interrupting atoms orgroups. In the present disclosure, unless otherwise specified, whenreferring to “interrupted”, it is meant that the covalent bonds in thegroup defined thereby are replaced by 1, 2, 3 or more selected fromheteroatoms (O, N, S), C═O, S═O or SO₂. The position of the interruptionmay be any chemically achievable position, and when there are multipleinterrupting atoms or groups, the relative positions between themultiple interrupting atoms or groups are not limited as long as theyare chemically achievable.

The term “stereoisomer” refers to an isomer produced by the differentarrangement of atoms in a molecule in space, and includes cis-transisomers, enantiomers and conformers. All stereoisomers are within thescope of the present disclosure. The compounds of the present disclosuremay be a single stereoisomer or a mixture of other isomers such as aracemate, or a mixture of all other stereoisomers.

The term “salt” refers to a pharmaceutically acceptable salt formed by acompound of the present disclosure with an acid, which may be an organicor inorganic acid, specifically selected from, for example, phosphoricacid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid,maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid,acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonicacid, malic acid, methanesulfonic acid or analogues thereof.

The term “solvate” refers to a form of a compound of the presentdisclosure that forms a solid or liquid complex by coordination with asolvent molecule. Hydrates are a special form of solvates in whichcoordination occurs with water. Within the scope of the presentdisclosure, the solvate is preferably a hydrate.

The term “crystal” refers to the various solid forms formed by thecompounds described herein, including crystalline forms and amorphousforms.

The term “hydrocarbyl” refers to alkyl or alkenyl.

The term “alkyl” refers to a linear, branched or cyclic saturatedsubstituent consisting of carbon and hydrogen. It has preferably 1 to 20carbon atoms, more preferably 1 to 12 carbon atoms. The term “alkyl”refers to a linear, branched or cyclic saturated hydrocarbyl group. Thealkyl group specifically includes, for example, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl,n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl,2,2,-methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl. The term“C₁₋₂₀ alkyl” refers to a linear, branched or cyclic saturatedhydrocarbyl group containing 1 to 20 carbon atoms. When an alkyl groupis substituted, the substituent may substitute at any availableattachment point, and the substitution may be mono-substitution orpoly-substitution. For example, the substituent can be selected fromalkyl, alkenyl, alkoxy, alkylthio, alkylamino, deuterum, halogen, thiol,hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl,cycloalkoxy, heterocycloalkoxy, cycloalkylthio or oxo.

The term “alkenyl” refers to a linear, branched or cyclic unsaturatedhydrocarbyl group containing a double bond, preferably containing 2 to20 carbon atoms, more preferably 2 to 12 carbon atoms. When it issubstituted, the substituent may substitute at any available attachmentpoint, and the substitution may be mono-substitution orpoly-substitution. For example, the substituent can be selected fromalkyl, alkenyl, alkoxy, alkylthio, alkylamino, deuterum, halogen, thiol,hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl,cycloalkoxy, heterocycloalkoxy, cycloalkylthio or oxo.

The term “cycloalkyl” refers to a saturated monocyclic cyclohydrocarbylgroup. A single ring generally includes 3 to 10 carbon atoms.Non-limiting examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl and the like. In the present disclosure,spiro cycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkylgroups are collectively referred to as polycyclic cycloalkyl groups.

The term “ring”, unless otherwise specified, means any cyclic structure,and is not limited to any form and composition, and may be any form of amonocyclic ring, a bridged ring, a spiro ring, a fused ring, and apolycyclic ring, and may be a carbocyclic or heterocyclic ring or otherforms of rings, such as a carbocyclic ring interrupted by carbonyl, andmay be unsubstituted or substituted. When referring to “a ringcontaining a particular atom or group” means that the particular atom orgroup is part of the ring itself. For example, “the sixth ring containsC═O” means that the constituent group of the ring itself constitutingthe sixth ring contains C═O, and if only the substituent on the ringcontains C═O, it is not among them.

The term “carbocyclyl” or “carbocyclic ring” refers to a carbocyclicgroup having 3 to 20 carbon atoms, preferably 3 to 16 carbon atoms, morepreferably 4 to 12 carbon atoms, and includes cycloalkyl, cycloalkenyl,aryl, bicyclic carbocyclyl, polycyclic carbocyclyl, and the like. Theterm “heterocyclyl” or “heterocyclic ring” means that the ringstructurally contains at least one heteroatom, and may specifically be,for example, heteroaryl, non-aromatic heterocyclyl, bicyclicheterocyclyl and polycyclic heterocyclyl containing one or moreidentical or different heteroatoms selected from O, S and N, etc.

The term “aryl” is to be understood broadly and includes not onlycarbocyclic aryl but also heteroaryl.

The term “carbocyclic aryl” refers to a 6- to 10-membered all-carbonmonocyclic or polycyclic aromatic group, including phenyl, naphthyl,biphenyl, and the like. The carbocyclic aryl group can be substituted orunsubstituted. The substituent is independently selected from alkyl,cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, etc.),alkenyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino,halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl,cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio,alkylsilyl and so on.

The term “heteroaryl” refers to a group of a heteroaromatic systemcontaining 1 to 10 heteroatoms, including monocyclic aryl and fused-ringaryl. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and thelike. Wherein monoheterocyclic groups include, but not limited to,furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole,1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine,tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine,isoxazolin, and the like. Fused heterocyclic groups include, but notlimited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene,purine, acridine, carbazole, fluorene, chromenone, fluorenone,quinoxaline, 3, 4-dihydronaphthalenone, dibenzofuran, hydrogenateddibenzofuran, benzoxazolyl, and the like. Heteroaryl groups can besubstituted or unsubstituted. The substituent is, for example, selectedfrom alkyl, cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl,etc.), alkenyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino,halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl,cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio,alkylsilyl and so on.

The term “hydrogen”, when not specifically stated, includes all isotopesof hydrogen, specifically can be protium (H), deuterium (D) or tritium(T), and preferably, hydrogen at different positions is independentlyselected from protium or deuterium. Wherein, the “hydrogen” in theactive hydrogen position is protium. The term “deuterium” is an isotopeof protium, the atomic mass is twice of that of the latter, and thebinding to carbon is stronger. “Deuterated” and “deuterium” means thatprotium is replaced with deuterium at the specified position.

The term “haloalkyl” refers to an alkyl group substituted by at leastone halogen atom.

The term “heterocyclic group” means a cyclic group containing at leastone hetero atom, wherein the hetero atom is nitrogen, oxygen, sulfur,and the like. The heterocyclic groups include monoheterocyclic groupsand polyheterocyclic groups.

The term “heteroatom”, when not specifically indicated, generallyincludes nitrogen, oxygen and sulfur.

The term “halogen”, when not specifically indicated, generally includesfluorine, chlorine, bromine and iodine, preferably fluorine, chlorineand bromine, and further preferably fluorine.

The term “plurality”, “multiple” or “more”, when used to define thenumber of substituents or interrupting atoms/groups, generally does notexceed the number of chemically replaceable groups or the number ofbonds that can be interrupted, more specifically, “plurality”,“multiple” or “more” preferably refers to a number less than or equal to6, more preferably less than or equal to 5, and further preferably lessthan or equal to 4.

The term “optional” or “optionally” comprises two parallel schemes,“selected” and “not selected”. For example, “the sixth ring optionallycontains C═O” means that the sixth ring contains C═O or does not containC═O.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The following embodiments are intended to provide a more completeunderstanding of the present disclosure, and are not intended to limitthe present disclosure in any way. The structures of all compounds weredetermined by¹+1 NMR or MS.

The compound names used in the embodiments are abbreviated as follows:

DCM: dichloromethane; EA: ethyl acetate; DMF: dimethylformamide; THF:tetrahydrofuran; TEA: triethylamine

T3P: 1-propylphosphoric anhydride; Boc-hydrazine: tert-butoxycarbonylhydrazine;

HATU: 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronhexafluorophosphate

TFA: trifluoroacetic acid

DMA: N,N-dimethylacetamide

DPPP: 1,3-bis(diphenylphosphino)propane

DPPA: diphenylphosphoryl azide

DBU: 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene

DIPEA: N,N-diisopropylethylamine

The present disclosure will be further described below in conjunctionwith specific embodiments:

Embodiment 1: Preparation of Compound I-1

Preparation of Compound 1b: In 20 mL DMF, Compound 1a (2.0 g, 8.1 mmol),DBU (1.85 g, 12.2 mmol) and ethyl iodide (2.28 g, 14.6 mmol) werereacted at room temperature for 16 hours. Then the mixture was dilutedwith 100 mL water, and extracted with EA. The organic phases werecombined, washed sequentially with sodium thiosulfate, 0.5N HCl andbrine, dried over anhydrous sodium sulfate, and then concentrated togive 2.1 g oily product, i.e., Compound 1b.

Preparation of Compound 1c: In N,N-dimethylacetamide (20 mL), Compound1b (2.1 g, 7.7 mmol), Boc-hydrazine (1.53 g, 11.6 mmol) and pyridiniump-toluenesulfonate (5.78 g, 23.1 mmol) were reacted at 60° C. for 16hours. After the reaction finished, the mixture was added with 100 mLwater, and then extracted with ethyl acetate (50 mL×3). The organicphases were combined, washed with brine, dried over anhydrous sodiumsulfate and concentrated to give a crude product, which was purified bycolumn chromatography to give 1.9 g yellow oily product, i.e., Compound1c. ESI-MS m/z 389.2 (M+H)+

Preparation of Compound 1d: Compound 1c (1.9 g, 4.9 mmol) was dissolvedin 10 mL ethanol, and 1N aq. NaOH solution (14.7 mL, 14.7 mmol) wasadded, and then the mixture was reacted at 60° C. for 24 hours. Themixture was acidified with 3N HCl and extracted with DCM. The organicphases were combined, washed with brine, dried and concentrated. Thecrude product was triturated in dichloromethane/petroleum ether (5 mL/50mL) to give 1.1 g white solid, i.e., Compound 1d. ESI-MS m/z 361.2(M+H)+

Preparation of Compound 1f: In DCM, Compound 1d (360 mg, 1 mmol),Compound 1e (133 mg, 1.2 mmol), TEA (303 mg, 3.0 mmol) and HATU (570 mg,1.5 mmol) were stirred at room temperature overnight, then diluted withwater, and extracted with DCM. The organic phases were combined, washedwith brine, dried and concentrated, and purified by columnchromatography to give 350 mg white solid, i.e., Compound 1f. ESI-MS m/z454.2 (M+H)+

Preparation of Compound 1g: Compound 1f (350 mg, 0.77 mmol) wasdissolved in 4 mL DCM, added with 1 mL TFA, and reacted at 0° C. for 6hours. The mixture was concentrated, and 1N NaOH was added till basic,and the mixture was extracted with DCM/iPrOH. The organic phases werecombined, washed with brine, dried and concentrated to give 210 mg oilyproduct, which was directly used in the next step.

Preparation of Compound 1h: Compound 1g (210 mg, 0.59 mmol) wasdissolved in 5 mL toluene. 30 mg paraformaldehyde and 100 mg acetic acidwas added, and the mixture was reacted at 100° C. for 3 hours. Themixture was concentrated and separated by thin layer chromatography togive 145 mg product. ESI-MS m/z 366.2 (M+H)+

Preparation of Compound 1j: Compound 1h (140 mg, 0.38 mmol) and Compound1i (114 mg, 0.5 mmol) were reacted in a solution of T3P in ethyl acetateat 100° C. for 3 hours in a pressured reactor. The mixture was cooled,diluted with saturated NaHCO₃, and then extracted with ethyl acetate.The organic phases were combined, dried and concentrated, and separatedby silica gel plate to give 170 mg product. ESI-MS m/z 576.2 (M+H)+.

Preparation of Compound I-1: In 5 mL DMA, Compound 1j (170 mg, 0.29mmol) and lithium chloride (50 mg, 1.18 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give120 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.46-7.53 (m, 2H), 7.36 (s,2H), 7.13-7.17 (m, 3H), 6.89 (s, 1H), 6.76 (s, 1H), 5.76-5.88 (m, 2H),5.14 (s, 1H), 4.88-4.91 (m, 1H), 4.77-4.80 (m, 1H), 4.48-4.51 (m, 1H),3.66-3.69 (m, 1H), 2.30 (s, 2H), 2.16 (s, 2H), 1.78-1.90 (m, 6H); ESI-MSm/z 486.2 (M+H)+.

Embodiment 2: Preparation of Compound I-5

Preparation of Compound 2b: Compound 1h (180 mg, 0.49 mmol) and Compound2a (264 mg, 1.0 mmol) were reacted in a solution of T3P in ethyl acetateat 100° C. for 3 hours in a pressured reactor. The mixture was cooled,diluted with saturated NaHCO₃ aqueous solution, and then extracted withethyl acetate. The organic phases were combined, dried and concentrated,and separated by silica gel plate to give 190 mg product. ESI-MS m/z612.2 (M+H)+.

Preparation of Compound 1-5: In 5 mL DMA, Compound 2b (190 mg, 0.31mmol) and lithium chloride (50 mg, 1.18 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give136 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.04-7.12 (m, 3H), 7.00-7.02(d, 1H, J=7.6 Hz), 6.90-6.93 (m, 1H), 6.79-6.83 (m, 1H), 6.63-6.64 (d,1H, J=7.2 Hz), 5.74-5.76 (d, 1H, J=7.6 Hz), 5.42-5.46 (m, 1H), 5.06 (s,1H), 4.82-4.86 (m, 1H), 4.69-4.77 (m, 1H), 4.37-4.40 (m, 1H), 4.04-4.07(m, 1H), 2.18-2.28 (m, 2H), 2.06-2.09 (m, 2H), 1.74-1.85 (m, 6H); ESI-MSm/z (M+H)+522.2.

Embodiment 3: Preparation of Compound I-7

Preparation of Compound 3b: Compound 3a (5.0 g, 27.8 mmol) was added ton-butyl vinyl ether (10 mL), then added with palladium trifluoroacetate(100 mg, 0.3 mmol), triethylamine (3.03 g, 30 mmol) and DPPP (124 mg,0.3 mmol), and stirred at 75° C. overnight in a pressured reactor. TLCshowed the reaction was complete. The mixture was added with 50 mL waterand extracted with ethyl acetate twice, and the organic phase was washedwith brine, dried over anhydrous sodium sulfate, concentrated andseparated by column chromatography to give 4.8 g product, which wasdirectly used in the next step.

Preparation of Compound 3c: Compound 3b (4.8 g, 23.3 mmol) was dissolvedin 50 mL anhydrous toluene, and added with 1N diethylzinc solution (70mL, 70 mmol) at −40° C. under nitrogen protection. After addition, themixture was stirred for 1 hour, and then added with chloroiodomethane(8.22 g, 46.6 mmol). After addition, the mixture was stirred for 2hours, slowly heated to room temperature and stirred overnight. TLCshowed the reaction was complete, and then the reaction mixture waspoured into ammonium chloride solution, and then extracted with ethylacetate (100 mL×3). The organic phases were combined, dried overanhydrous sodium sulfate and concentrated to give 4.9 g crude product.

Preparation of Compound 3d: Intermediate 3c (4.9 g, 22.2 mmol) wasdissolved in 50 mL methanol, added with aqueous sodium hydroxide, andstirred at room temperature for 5 hours. TLC showed starting materialconsumed. HCl was added to adjust pH=2-3 and the mixture was extractedwith ethyl acetate (100 mL×3). The organic phases were concentrated togive 2.3 g crude product.

Preparation of Compound 3e: Compound 3d (2.3 g, 17.7 mmol) was dissolvedin 15 mL toluene, added with DPPA (5.84 g, 21.2 mmol) and TEA (3.58 g,35.4 mmol), stirred at room temperature for 2 hours, then added withbenzyl alcohol (5.73 g, 53.1 mmol), and reacted at 90° C. for 2 hours.TLC showed the reaction was complete, and the mixture was cooled to roomtemperature, and added with 100 mL water to quench the reaction,extracted with ethyl acetate (80 mL×3), and the organic phases werecombined, dried and concentrated to give a crude product, which ranthrough column chromatography to give 1.5 g mixture of product andbenzyl alcohol that directly used in the next step.

Preparation of Compound 3f: 1.5 g crude of Compound 3e was dissolved in10 mL methanol, and added with 150 mg Pd/C and 0.2 mL concentratedhydrochloric acid. The mixture was replaced with hydrogen for threetimes and was reacted for 5 hours. TLC showed the reaction was complete,and the mixture was filtered through diatomite, and the filtrate wasadded with HCl to adjust pH=1-2, and concentrated to dry to give 0.6 gproduct, which was directly used in the next step.

Preparation of Compound 3h: In 15 mL dichloromethane, Compound 3f (0.6g, 4.36 mmol), Compound 3g (1.12 g, 4.0 mmol), HATU (1.82 g, 4.8 mmol)and TEA (1.21 g, 12.0 mmol) were stirred at room temperature over night.TLC showed the reaction was complete, and the mixture was added with 20mL water and extracted with dichloromethane (30 mL×2), and the organicphases were combined, dried and concentrated to give a crude product,which was separated by column chromatography to give 0.85 g product.

Preparation of Compound 3i: In 5 mL DMF, Compound 3h (0.85 g, 2.6 mmol),potassium carbonate (718 mg, 5.2 mmol) and2,4-dinitrophenylhydroxylamine (0.78 g, 3.9 mmol) were stirred at roomtemperature for 5 hours. TLC showed the reaction was complete, and themixture was added with 20 mL water and extracted with dichloromethane(20 mL×3), and the organic phases were combined, dried and concentratedto give a crude product, which was separated by column chromatography togive 0.73g product.

Preparation of Compound 3j: Compound 3i (0.73 g, 2.1 mmol), acetic acid(120 mg, 2.1 mmol) and paraformaldehyde (0.23g, 2.52 mmol) were refluxedin toluene for 2 hours. TLC showed the reaction was complete. Themixture was concentrated, and the residue was added with 10 mL water andextracted with dichloromethane (20 mL×3), and the organic phases werecombined, dried and concentrated to give a crude product, which wasseparated by column chromatography to give 0.45g product.

Preparation of Compound 3k: In 3 mL solution of T3P in ethyl acetate,Compound 3j (450 mg, 1.27 mmol) and Compound 2a (660 mg, 2.54 mmol) werereacted at 100° C. for 3 hours in a pressured reactor. The mixture wascooled, diluted with saturated NaHCO₃, and then extracted with ethylacetate. The organic phases were combined, dried and concentrated, andseparated by column chromatography to give 290 mg product. ESI-MS m/z602.2 (M+H)⁺.

Preparation of Compound 1-7: In 5 mL DMA, Compound 3k (290 mg, 0.48mmol) and lithium chloride (50 mg, 1.18 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give187 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.05-7.15 (m, 3H), 7.00-7.02(d, 1H, J=8.0 Hz), 6.94-6.98 (m, 1H), 6.81-6.85 (m, 1H), 6.65-6.67 (d,1H, J=8.0 Hz), 5.80-5.82 (d, 1H, J=8.0 Hz), 5.38-5.42 (m, 1H), 5.13 (s,1H), 4.96-5.00 (m, 1H), 4.21-4.27 (m, 2H), 4.02-4.06 (m, 1H), 3.61-3.67(m, 2H), 3.22-3.25 (m, 1H), 2.84-2.91 (m, 1H), 0.44-0.47 (m, 4H); ESI-MSm/z (M+H)⁺ 512.2.

Embodiment 4: Preparation of Compound I-8

Preparation of Compound 4b: In 30 mL dimethyl sulfoxide, Compound 4a(2.24g, 28.7 mmol), bromocyclopropane (3.47g, 28.7 mmol) and potassiumt-butoxide (3.22g, 28.7 mmol) were reacted at 80° C. overnight. Themixture was cooled to room temperature, and added with saturated NaHCO₃solution to quench the reaction, and extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with brine, dried andconcentrated to give 2.8 g yellow liquid. It was directly used in thenext step.

Preparation of Compound 4c: In 20 mL tetrahydrofuran, Compound 4b(1.60g, 13.6 mmol), phthalimide (2.39 g, 16.2 mmol), triphenylphosphine(5.34 g, 20.4 mmol) and isopropyl azodicarboxylate (4.12 g, 20.4 mmol)were reacted at room temperature overnight. The mixture was added withwater to quench the reaction, and extracted with ethyl acetate (20mL×3). The organic phases were combined, washed with brine, dried andconcentrated to give a crude product, which was separated by columnchromatography to give 2.4 g oily product. It was directly used in thenext step.

Preparation of Compound 4d: Compound 4c (2.40 g, 10 mmol) was dissolvedin 30 mL methanol, 2 g hydrazine hydrate was added, and then the mixturewas reacted at 75° C. for 2 hours. TLC showed the reaction was complete.The mixture was cooled and filtered. The filtrate was concentrated andtriturated with ethyl ether. The mixture was filtered, and the filtratewas dried to give 1.04 g crude product. It was directly used in the nextstep.

Preparation of Compound 4e: In 10 mL dichloromethane, Compound 4d (420mg, 3.6 mmol), Compound 3g (864 mg, 2.4 mmol), HATU (1.37 g, 3.6 mmol)and TEA (720 mg, 7.2 mmol) were stirred at room temperature over night.TLC showed the reaction was complete, and the mixture was added with 30mL water and extracted with dichloromethane (30 mL×2), and the organicphases were combined, dried and concentrated to give a crude product,which was separated by silica gel plate to give 900 mg product. ESI-MSm/z (M+H)⁺ 344.1.

Preparation of Compound 4f: In 5 mL DMF, Compound 4e (900 mg, 2.4 mmol),potassium carbonate (1.08 g, 7.8 mmol) and2,4-dinitrophenylhydroxylamine (780 mg, 3.9 mmol) were stirred at 60° C.for 5 hours. The mixture was added with 20 mL water and extracted withdichloromethane (20 mL×3), and the organic phases were combined, driedand concentrated to give a crude product, which was separated by silicagel plate to give 120 mg product.

Preparation of Compound 4g: Compound 4f (120 mg, 0.33 mmol), acetic acid(36 mg, 0.06 mmol) and paraformaldehyde (100 mg, 1.1 mmol) were refluxedin toluene for 6 hours. The mixture was concentrated, and the residuewas added with 10 mL water and extracted with dichloromethane (20 mL×3),and the organic phases were combined, dried and concentrated to give acrude product, which was separated by silica gel plate to give 85 mgproduct.

Preparation of Compound 4h: In 2 mL solution of T3P in ethyl acetate,Compound 4g (85 mg, 0.23 mmol) and Compound 2a (90 mg, 0.34 mmol) werereacted at 100° C. for 3 hours in a pressured reactor. The mixture wascooled, diluted with saturated sodium bicarbonate, and then extractedwith ethyl acetate. The organic phases were combined, dried andconcentrated, and separated by column chromatography to give 20 mgproduct.

Preparation of Compound 1-8: In 1 mL DMA, Compound 4h (20 mg, 0.03 mmol)and lithium chloride (50 mg, 1.18 mmol) were reacted at 100° C. for 3hours. After the reaction finished, the mixture was diluted with 10 mLwater, and added with 2N hydrochloric acid to adjust pH to 3-4. Themixture was filtered, and the solid was dried under vacuum to give 5 mgproduct. ¹HNMR (400 MHz, CDCl₃) δ: 7.02-7.12 (m, 5H), 6.85 (m, 1H), 6.77(m, 1H), 5.81 (d, 1H, J=7.6 Hz), 5.43 (m, 1H), 5.20 (s, 1H), 5.10 (d,1H, J=12.8 Hz), 4.25 (d, 1H, J=12.8 Hz), 4.06 (d, 2H, J=14 Hz), 3.31 (m,1H), 2.73 (t, 2H, J=6.8 Hz), 1.95 (m, 1H), 0.89 (m, 2H), 0.56 (m, 2H);ESI-MS m/z (M+H)⁺ 528.1.

Embodiment 5: Preparation of Compound I-14

Preparation of Compound 5b: In DCM, Compound 1d (360 mg, 1 mmol),Compound 5a (116 mg, 1.2 mmol), TEA (303 mg, 3.0 mmol) and HATU (570 mg,1.5 mmol) were stirred at room temperature overnight, then diluted withwater, and extracted with DCM. The organic phases were combined, washedwith brine, dried and concentrated, and separated by columnchromatography to give 320 mg white solid.

Preparation of Compound 5c: Compound 5b (320 mg, 0.73 mmol) wasdissolved in 4 mL DCM, added with 1 mL TFA, and reacted at 0° C. for 6hours. The mixture was dried, added with 1N NaOH to adjust to bealkaline, and extracted with DCM/iPrOH. The organic phases werecombined, washed with brine, dried and concentrated to give 195 mg oilyproduct, which was directly used in the next step.

Preparation of Compound 5d: Compound 5c (195 mg, 0.57 mmol) wasdissolved in 5 mL toluene, added with 30 mg paraformaldehyde and 100 mgacetic acid, and reacted at 100° C. for 3 hours. The mixture wasconcentrated and separated by thin layer chromatography to give 130 mgproduct.

Preparation of Compound 5e: In a solution of T3P in ethyl acetate,Compound 5d (130 mg, 0.37 mmol) and Compound 2a (114 mg, 0.5 mmol) werereacted at 100° C. for 3 hours in a pressured reactor. The mixture wascooled, diluted with saturated sodium bicarbonate, and then extractedwith ethyl acetate. The organic phases were combined, dried andconcentrated, and separated by silica gel plate to give 130 mg product.

Preparation of Compound 1-14: In 1 mL DMA, Compound 5e (130 mg, 0.23mmol) and lithium chloride (50 mg, 1.18 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 3-4.The mixture was filtered, and the solid was dried under vacuum to give35 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.03-7.11 (m, 4H), 6.94 (m,1H), 6.82 (m, 1H), 6.67 (m, 1H), 5.78 (d, 1H, J=7.6 Hz), 5.43 (d, 1H,J=12.8 Hz), 5.19 (t, 1H, J=7.6 Hz), 5.12 (s, 1H), 4.93 (d, 1H, J=13.2Hz), 4.56 (d, 1H, J=13.6 Hz), 4.08 (d, 1H, J=14 Hz), 2.24 (m, 1H), 2.13(m, 3H), 0.54 (t, 2H, J=8.0 Hz), 0.34 (m, 2H); ESI-MS m/z (M+H)⁺508.2.

With the same way, the following compounds were synthesized:

Com- LCMS pound Structure ([M + H]⁺) Purity I-9

472.2 96% I-10

488.2 93% I-21

504.2 95%

Embodiment 6: Preparation of Compound I-65

Preparation of Compound 6b: In 5 mL dichloromethane, Compound 6a (600mg, 2.13 mmol), Compound 3g (280 mg, 2.34 mmol), HATU (1.21 g, 3.20mmol) and TEA (850 mg, 8.5 mmol) were stirred at room temperature overnight. TLC showed the reaction was complete, and the mixture was addedwith 20 mL water and extracted with dichloromethane (30 mL×3), and theorganic phases were combined, dried and concentrated to give a crudeproduct, which was separated by column chromatography to give 455 mgproduct.

Preparation of Compound 6c: In 15 mL DMF, Compound 6b (455 mg, 1.46mmol), potassium carbonate (543 mg, 4.38 mmol) and2,4-dinitrophenylhydroxylamine (392 mg, 2.19 mmol) were stirred at roomtemperature for 16 hours. TLC showed the reaction was complete, and themixture was added with 20 mL water and extracted with dichloromethane(20 mL×3), and the organic phases were combined, dried and concentratedto give a crude product, which was separated by silica gel plate to give200 mg product. ESI-MS m/z (M+H)⁺ 326.1

Preparation of Compound 6d: Compound 6c (200 mg, 0.62 mmol), acetic acid(200 mg, 3.3 mmol) and paraformaldehyde (18 mg, 0.62 mmol) were refluxedin 10 mL toluene for 2 hours. TLC showed the reaction was complete. Themixture was concentrated, and the residue was added with 10 mL water andextracted with dichloromethane (20 mL×3), and the organic phases werecombined, dried and concentrated to give a crude product, which wasseparated by column chromatography to give 190 mg product. ESI-MS m/z(M+H)⁺ 338.1

Preparation of Compound 6e: In 3 mL solution of T3P in ethyl acetate,Compound 6d (190 mg, 0.56 mmol) and Compound 2a (223 mg, 0.84 mmol) werereacted at 100° C. for 1.5 hours in a pressured reactor. The mixture wascooled, diluted with water, and then extracted with ethyl acetate. Theorganic phases were combined, dried and concentrated, and separated bysilica gel plate to give 227 mg product.

Preparation of Compound I-65: In 5 mL DMA, Compound 6e (227 mg, 0.4mmol) and lithium chloride (86 mg, 2.0 mmol) were reacted at 100° C. for3 hours. After the reaction finished, the mixture was diluted with 10 mLwater, and added with 2N hydrochloric acid to adjust pH to 5-6. Themixture was filtered, and the solid was dried under vacuum to give 100mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.10 (m, 3H), 6.99 (m, 2H), 6.84(m, 1H), 6.70 (m, 1H), 5.75 (d, 1H, J=7.6 Hz), 5.40 (d, 1H, J=15.2),5.14 (s, 1H), 4.82 (d, 1H, J=12.8 Hz), 4.25 (d, 1H, J=12.8 Hz), 4.04 (d,1H, J=14.0 Hz), 3.76 (m, 3H), 2.98 (m, 2H), 2.54 (s, 1H), 2.05-2.15 (m,6H); ESI-MS m/z (M+H)⁺ 494.1.

Embodiment 7: Preparation of Compound I-66

Preparation of Compound 7b: In 10 mL dichloromethane, Compound 7a (250mg, 1.82 mmol), Compound 3g (465 mg, 1.65 mmol), HATU (941 mg, 2.48mmol) and TEA (660 mg, 6.6 mmol) were stirred at room temperature overnight. TLC showed the reaction was complete, and the mixture was addedwith 20 mL water and extracted with dichloromethane (30 mL×3), and theorganic phases were combined, dried and concentrated to give a crudeproduct, which was separated by column chromatography to give 430 mgproduct.

Preparation of Compound 7c: In 15 mL DMF, Compound 7b (430 mg, 1.30mmol), potassium carbonate (538 mg, 3.9 mmol) and2,4-dinitrophenylhydroxylamine (391 mg, 1.96 mmol) were stirred at roomtemperature for 16 hours. TLC showed the reaction was complete, and themixture was added with 20 mL water and extracted with dichloromethane(20 mL×3), and the organic phases were combined, dried and concentratedto give a crude product, which was separated by silica gel plate to give220 mg product. ESI-MS m/z (M+H)⁺ 344.1

Preparation of Compound 7d: Compound 7c (220 mg, 0.64 mmol), acetic acid(200 mg, 3.3 mmol) and paraformaldehyde (20 mg, 0.64 mmol) were refluxedin 10 mL toluene for 2 hours. TLC showed the reaction was complete. Themixture was concentrated, and the residue was added with 10 mL water andextracted with dichloromethane (20 mL×3), and the organic phases werecombined, dried and concentrated to give a crude product, which wasseparated by silica gel plate to give 165 mg product. ESI-MS m/z (M+H)⁺356.1

Preparation of Compound 7e: In 3 mL solution of T3P in ethyl acetate,Compound 7d (165 mg, 0.46 mmol) and Compound 2a (184 mg, 0.70 mmol) werereacted at 100° C. for 1.5 hours in a pressured reactor. The mixture wascooled, diluted with water, and then extracted with ethyl acetate. Theorganic phases were combined, dried and concentrated, and separated bysilica gel plate to give 100 mg product.

Preparation of Compound 1-66: In 3 mL DMA, Compound 7e (100 mg, 0.17mmol) and lithium chloride (35 mg, 0.83 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give45 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.11 (m, 3H), 6.96 (m, 1H),6.82 (m, 1H), 6.63 (m, 1H), 5.98 (d, 1H, J=9.2 Hz), 5.39 (m, 1H),5.02-5.12 (m, 2H), 4.23 (d, 1H, J=12.8 Hz), 4.06 (d, 1H, J=14.0 Hz),2.39-2.49 (m, 5H); ESI-MS m/z (M+H)⁺512.1

Embodiment 8: Preparation of Compound I-77

Preparation of Compound 8b: In 10 mL dichloromethane, Compound 8a (250mg, 2.5 mmol), Compound 3g (705 mg, 2.5 mmol), HATU (1.19 g, 3.1 mmol)and TEA (1.01 g, 10.5 mmol) were stirred at room temperature over night.TLC showed the reaction was complete, and the mixture was added with 20mL water and extracted with dichloromethane (30 mL×3), and the organicphases were combined, dried and concentrated to give a crude product,which was separated by column chromatography to give 780 mg product.

Preparation of Compound 8c: In 10 mL DMF, Compound 8b (780 mg, 2.5mmol), potassium carbonate (1.04 g, 7.5 mmol) and2,4-dinitrophenylhydroxylamine (752 mg, 3.8 mmol) were stirred at roomtemperature for 16 hours. TLC showed the reaction was complete, and themixture was added with 20 mL water and extracted with dichloromethane(20 mL×3), and the organic phases were combined, dried and concentratedto give a crude product, which was separated by silica gel plate to give390 mg product. ESI-MS m/z (M+H)⁺ 326.1

Preparation of Compound 8d: Compound 8c (390 mg, 1.2 mmol), acetic acid(500 mg, 8.3 mmol) and paraformaldehyde (36 mg, 1.2 mmol) were refluxedin 10 mL toluene for 2 hours. TLC showed the reaction was complete. Themixture was concentrated, and the residue was added with 10 mL water andextracted with dichloromethane (20 mL×3), and the organic phases werecombined, dried and concentrated to give a crude product, which wasseparated by silica gel plate to give 280 mg product. ESI-MS m/z (M+H)⁺338.1

Preparation of Compound 8e: In 1.5 mL solution of T3P in ethyl acetate,Compound 8d (99 mg, 0.30 mmol) and Compound 2a (117 mg, 0.45 mmol) werereacted at 100° C. for 1.5 hours in a pressured reactor. The mixture wascooled, diluted with water, and then extracted with ethyl acetate. Theorganic phases were combined, dried and concentrated, and separated bysilica gel plate to give 150 mg product.

Preparation of Compound I-77: In 3 mL DMA, Compound 8e (150 mg, 0.26mmol) and lithium chloride (70 mg, 1.66 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give75 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.13-7.14 (m, 3H), 7.1-7.03 (d,2H, J=8.0), 6.84-6.88 (m, 1H), 6.70-6.72 (d, 1H, J=8.0), 5.81-5.83 (d,1H, J=8.0), 5.42-5.44 (m, 1H), 5.15 (s, 1H), 4.84-4.87 (m, 1H),4.29-4.32 (m, 1H), 4.06-4.09 (m, 1H), 2.09-2.19 (m, 7H); ESI-MS m/z(M+H)⁺ 494.1

With the same way, the following compounds were synthesized:

Compound Structure LCMS ([M + H]⁺) Purity I-69

458.2 95% I-81

476.1 94% I-83

476.2 97% I-85

476.2 97% I-89

492.1 96%

Embodiment 9: Preparation of Compound II-5

Preparation of Compound 9b: In a mixed solvent of DMF (7.5 ml) andtoluene (7.5 ml), Compound 9a (250 mg, 2.02 mmol), phthalic anhydride(300 mg, 2.02 mmol), triethylamine (408 mg, 4.04 mmol) were reacted at130° C. for 5 hours, and TLC showed the reaction was completed, and themixture was added with water and stirred for 1 hour, and filtered togive 332 mg white solid, which was directly used in the next step.

Preparation of Compound 9c: Compound 9b (332 mg, 1.53 mmol) andbromoacetaldehyde dimethyl acetal (517 mg, 3.06 mmol) were dissolved in15 ml DMA, heated to 40° C., and then added with sodium tert-butoxide(294 mg, 3.06 mmol), and the mixture was stirred at 40° C. for 5 hours.The mixture was cooled to room temperature, added with 10 mL water toquench the reaction, added with glacial acetic acid to adjust pH=3-4,extracted with ethyl acetate, dried, concentrated, and separated bycolumn chromatography to give 265 mg product.

Preparation of Compound 9d: Compound 9c (265 mg, 0.87 mmol) wasdissolved in 30 mL methanol, 2 g hydrazine hydrate was added, and thenthe mixture was reacted at 75° C. for 2 hours. TLC showed the reactionwas complete. The mixture was cooled and filtered. The filtrate wasconcentrated and triturated with ethyl ether. The mixture was filtered,and the filtrate was dried to give 96 mg crude product. It was directlyused in the next step.

Preparation of Compound 9e: In DCM, Compound 1d (137 mg, 0.38 mmol),Compound 9d (96 mg, 0.55 mmol), TEA (115 mg, 1.14 mmol) and HATU (289mg, 0.76 mmol) were stirred at room temperature overnight, then dilutedwith water, and extracted with DCM. The organic phases were combined,washed with brine, dried and concentrated, and separated by columnchromatography to give 155 mg product.

Preparation of Compound 9f: Compound 9e (155 mg, 0.3 mmol) was addedwith 18 mL acetonitrile and 3 mL water, and the mixture was heated to60° C., dropwise added with methanesulfonic acid (8 mg, 0.9 mmol) andreacted for 6h. TLC showed the reaction was complete. The mixture wasadded with sodium bicarbonate aqueous solution to be weakly alkaline,concentrated and extracted with dichloromethane, and the organic phaseswere combined, dried, concentrated and separated by silica gel plate togive 60 mg white solid.

Preparation of Compound 9g: In a solution of T3P in ethyl acetate,Compound 9f (60 mg, 0.17 mmol) and Compound 2a (69 mg, 0.26 mmol) werereacted at 100° C. for 3 hours in a pressured reactor. The mixture wascooled, diluted with saturated NaHCO₃, and then extracted with ethylacetate. The organic phases were combined, dried and concentrated, andseparated by chiral column to give 15 mg product.

Preparation of Compound II-5: In 1 mL DMA, Compound 9g (15 mg, 0.025mmol) and lithium chloride (10 mg, 0.24 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 3-4.The mixture was filtered, and the solid was dried under vacuum to give 5mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.28-7.34 (m, 1H), 7.09-7.16 (m,2H), 6.83-7.01 (m, 2H), 6.66-6.68 (d, 1H, J=8.0); 6.56-6.59 (m, 1H),5.77-5.90 (m, 1H), 5.28-5.37 (m, 1H), 5.02-5.18 (m, 1H), 4.61-4.71 (m,1H), 3.91-4.17 (m, 3H), 3.59-3.68 (m, 1H), 2.95-3.07 (m, 1H), 0.23-0.89(m, 4H); ESI-MS m/z (M+H)⁺ 510.1.

With the same way, the following compounds were synthesized:

Com- LCMS pound Structure ([M + H]⁺) Purity II-1

474.2 95% II-8

528.1 94% II-9

492.1 94% II-13

492.1 95% II-17

492.1 96%

Embodiment 10: Preparation of Compound II-6

Preparation of Compound 10a: Compound Ic (388 mg, 1 mmol) was dissolvedin 3 mL dichloromethane and added with 1 mL trifluoroacetic acid, andthe mixture was stirred at room temperature for 3 hours. TLC showed thereaction was complete, and the mixture was added with 3N sodiumhydroxide solution to adjust pH=9-10. The mixture was extracted withdichloromethane, and organic phases were combined, washed with brine,dried and concentrated to give 270 mg solid, which was directly used inthe next step.

Preparation of Compound 10c: Compound 10b (1.0 g, 7.8 mmol) wasdissolved in 10 mL anhydrous tetrahydrofuran and replaced with nitrogenfor three times. The mixture was cooled to −78° C. and 2.5Mn-butyllithium solution (3.1 mL, 7.8 mmol) was added slowly undernitrogen protection. After addition, the mixture was stirred at thistemperature for 2 hours. Then allyl chloroformate (0.94 g, 7.8 mmol) wasadded by dropwise. After addition, the mixture was stirred at thistemperature for 2 hours, and TLC showed the starting materials werecompletely reacted. The reaction mixture was poured into saturatedammonium chloride solution, and extracted with ethyl acetate (15 mL×3).The organic phases were combined, dried over anhydrous sodium sulfateand concentrated to give 1.65g oily product.

Preparation of Compound 10d: Compound 10c (1.65 g, 7.8 mmol) wasdissolved in 15 mL anhydrous tetrahydrofuran, and 1M diisobutylaluminumhydride solution (11.7 mL, 11.7 mmol) was added slowly at −78° C. undernitrogen protection. After addition, the mixture was stirred at thistemperature for 2 hours. TLC showed the starting materials werecompletely reacted. The reaction mixture was poured into saturatedammonium chloride solution, and extracted with ethyl acetate (20 mL×3).The organic phases were combined, dried over anhydrous sodium sulfateand concentrated to give 1.57g oily product.

Preparation of Compound 10e: Compound 10d (1.57 g, 7.4 mmol) wasdissolved in 15 mL methanol, and p-toluenesulfonic acid monohydrate (140mg, 0.74 mmol) was added. The mixture was stirred at room temperatureovernight. TLC showed the starting materials were completely reacted.The mixture was added with saturated sodium bicarbonate solution tillneutral, then concentrated. The residue was separated by columnchromatography to give 0.86 g yellow oily product.

Preparation of Compound 10f: Compound 10a (270 mg, 0.94 mmol) andCompound 10e (255 mg, 1.13 mmol) were dissolved in 5 mL acetonitrile.Under nitrogen protection and at −20° C., 1M solution of tintetrachloride in dichloromethane (1.4 mL, 1.41 mmol) was added dropwise.After addition, the mixture was stirred at this temperature for 3 hours.The mixture was added with saturated sodium bicarbonate solution,stirred for 30 min, and separated, The aqueous phase was extracted withdichloromethane. The organic phases were combined, washed with brine,dried and concentrated to give 428 mg crude product.

Preparation of Compound 10g: Compound 10f (428 mg, 0.89 mmol) wasdissolved in 5 mL tetrahydrofuran, andtetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol) and morpholine(774 mg, 8.9 mmol) were added and reacted at room temperature for 2hours. TLC showed the reaction was complete. The mixture wasconcentrated, and the residue was separated by column chromatography togive 216 mg product.

Preparation of Compound 10h: In 3 mL solution of T3P in ethyl acetate,Compound 10g (216 mg, 0.61 mmol) and Compound 2a (242 mg, 0.92 mmol)were reacted at 100° C. for 3 hours in a pressured reactor. The mixturewas cooled, diluted with saturated NaHCO₃, and then extracted with ethylacetate. The organic phases were combined, dried and concentrated, andseparated by column chromatography to give 200 mg crude product, whichwas separated by chiral column to give 40 mg product.

Preparation of Compound II-6: In 1 mL DMA, Compound 10h (40 mg, 0.067mmol) and lithium chloride (20 mg, 0.48 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 3-4.The mixture was filtered, and the solid was dried under vacuum to give25 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.05-7.15 (m, 5H), 6.85 (m,1H), 6.70 (d, 1H, J=7.6 Hz), 5.78 (d, 1H, J=7.6 Hz), 5.3 (m, 2H), 4.69(d, 1H, J=6.8 Hz), 4.17 (d, 1H, J=14 Hz), 4.09 (d, 1H, J=14 Hz), 3.90(m, 1H), 3.69 (m, 1H), 3.44 (d, 1H, J=15.2 Hz), 0.95 (m, 1H), 0.74 (m,3H); ESI-MS m/z (M+H)⁺ 510.1.

With the same way, the following compounds were synthesized:

Compound Structure LCMS ([M + H]⁺) Purity II-2

474.2 95% II-7

526.2 94% II-10

492.1 95% II-14

492.1 96% II-18

492.1 95% II-22

508.1 96% II-29

528.1 96%

Embodiment 11: Preparation of Compound II-66

Preparation of Compound 11c: In 100 mL dichloromethane, Compound 11a(5.00 g, 58 mmol), Compound 11b (5.98 g, 64 mmol), HATU (33.0 g, 87mmol) and DIPEA (30 mL, 174 mmol) were stirred at room temperatureovernight. TLC showed the reaction was complete, and the mixture wasadded with 100 mL water and extracted with dichloromethane (30 mL×3),and the organic phases were combined, dried and concentrated to give acrude product, which was separated by column chromatography to give 6.0gproduct.

Preparation of compound IId: Compound 11c (1.00 g, 8.0 mmol) wasdissolved in 240 mL dichloromethane, then added Grubbs II catalyst (260mg, 0.32 mmol), and refluxed for 12 hours under nitrogen protection. TLCshowed the reaction was complete, and the mixture was concentrated togive a crude product, which was separated by column chromatography togive 150 mg product.

Preparation of Compound 11e: Compound 11d (150 mg, 1.54 mmol) wasdissolved in 4 mL anhydrous tetrahydrofuran, and replaced with nitrogenfor three times. The mixture was cooled to −78° C. and 2.5Mn-butyllithium solution (0.62 mL, 1.54 mmol) was added slowly under N2atmosphere. After addition, the mixture was stirred at this temperaturefor 2 hours. Then allyl chloroformate (186 mg, 1.54 mmol) was added bydropwise. After addition, the mixture was stirred for 2 hours, and TLCshowed reaction complete. The reaction mixture was poured into saturatedammonium chloride solution and then extracted with ethyl acetate (15mL×3). The organic phases were combined, dried over anhydrous sodiumsulfate and concentrated to give 235 mg oily product.

Preparation of Compound 11f: Compound 11e (235 mg, 1.3 mmol) wasdissolved in 3 mL anhydrous tetrahydrofuran, and 1M diisobutylaluminumhydride solution (1.7 mL, 1.7 mmol) was added slowly at −78° C. undernitrogen protection. After addition, the mixture was stirred at thistemperature for 2 hours. TLC showed reaction complete. The reactionmixture was poured into saturated potassium sodium tartrate solution,and extracted with ethyl acetate (20 mL×3). The organic phases werecombined, dried over anhydrous sodium sulfate and concentrated to give200 mg oily product.

Preparation of Compound 11g: Compound 11f (200 mg, 1.1 mmol) wasdissolved in 3 mL methanol, and p-toluenesulfonic acid monohydrate (21mg, 0.11 mmol) was added, and the mixture was stirred at roomtemperature for 5 hours. TLC showed reaction complete. The mixture wasadded with saturated sodium bicarbonate solution till neutral, andextracted with dichloromethane (20 mL×3). The organic phases werecombined, dried over anhydrous sodium sulfate and concentrated to give acrude product, which was separated by column chromatography to give 180mg oily product.

Preparation of Compound 11h: Compound 11g (180 mg, 0.65 mmol) andCompound 10a (150 mg, 0.75 mmol) were dissolved in 15 mL acetonitrile.Under nitrogen protection and at −20° C., 1M solution of tintetrachloride in dichloromethane (0.95 mL, 0.95 mmol) was addeddropwise. After addition, the mixture was stirred at this temperaturefor 3 hours. The mixture was added with saturated sodium bicarbonatesolution, stirred for 30 min, and separated. The aqueous phase wasextracted with dichloromethane. The organic phases were combined, washedwith brine, dried and concentrated to give 300 mg solid. The solid wasdissolved in 5 mL tetrahydrofuran, andtetrakis(triphenylphosphine)palladium (55 mg, 0.065 mmol) and morpholine(5 g, 55 mmol) were added and reacted at room temperature for 2 hours.TLC showed the reaction was complete. The mixture was concentrated, andthe residue was separated by column chromatography to give 150 mgproduct.

Preparation of Compound 11i: In 3 mL solution of T3P in ethyl acetate,Compound 11h (70 mg, 0.22 mmol) and Compound 2a (86 mg, 0.32 mmol) werereacted at 100° C. for 1.5 hours in a pressured reactor. The mixture wascooled, diluted with saturated NaHCO₃, and extracted with ethyl acetate.The organic phases were combined, dried and concentrated, and separatedby column chromatography to give 100 mg crude product.

Preparation of Compound II-66: In 3 mL DMA, Compound 11i (100 mg, 0.18mmol) and lithium chloride (37 mg, 0.88 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and 2N hydrochloric acid was added to adjust pH to 3-4. Themixture was filtered, and the solid was dried under vacuum to give 30 mgproduct. ¹HNMR (400 MHz, CDCl₃) δ: 7.28 (d, 2H, J=8.0 Hz), 7.21 (m, 1H),7.05-7.15 (m, 5H), 6.98-7.01 (m, 1H), 6.91 (q, 1H, J=8.4 Hz), 6.85 (m,1H), 6.69 (m, 1H), 6.63 (m, 1H), 5.88 (d, 1H, J=7.6 Hz), 5.78 (d, 1H,J=7.6 Hz), 5.69 (m, 4H), 5.46 (m, 1H), 5.32 (m, 1H), 5.28 (s, 1H), 5.15(s, 1H), 5.03 (m, 2H), 4.62 (dd, 1H, J=3.6, 11.2 Hz), 4.49 (dd, 1H,J=4.0, 10.8 Hz), 4.07 (t, 2H, J=14.4 Hz), 3.44 (d, 1H, J=18.8 Hz), 3.27(m, 1H), 2.57 (m, 2H), 2.30 (m, 2H); ESI-MS m/z (M+H)⁺ 480.1.

With the same way, the following compounds were synthesized:

Compound Structure LCMS ([M + H]⁺) Purity II-34

538.2 96% II-65

494.1 94% II-67

512.2 93%

Embodiment 12: Preparation of Compound II-101

Preparation of Compound 12b: In 10 mL tetrahydrofuran, Compound 12a (520mg, 2.6 mmol), Compound 10a (570 mg, 2.0 mmol) and DBU (490 mg, 3.3mmol) were stirred at 55° C. overnight. The mixture was concentrated,added with 30 mL water and extracted with ethyl acetate (30 mL×3), andthe organic phases were combined, dried and concentrated to give a crudeproduct, which was separated by column chromatography to give 720 mgproduct.

Preparation of Compound 12c: Compound 12b (720 mg, 1.6 mmol), ethylglyoxalate (50% toluene solution, 1.66 g, 8.3 mmol) and acetic acid (20mg, 0.3 mmol) were refluxed in 10 mL toluene for 6 hours. After thereaction was complete, the mixture was diluted with 30 mL ethyl acetate,and washed with sodium bicarbonate solution and brine. The organicphases were dried and concentrated to give a crude product, which wasseparated by column chromatography to give 450 mg product.

Preparation of Compound 12d: Compound 12c (400 mg, 0.76 mmol) wasdissolved in 15 mL dichloromethane and added with 5 mL trifluoroaceticacid, and the mixture was stirred at room temperature for 2 hours. Themixture was dried and added with 10 mL water, cooled in ice-water bath,added with saturated sodium bicarbonate solution to pH=9-10, and stirredat room temperature overnight. The reaction solution was extracted withdichloromethane and the organic phases were dried and separated bysilica gel plate to give 150 mg product.

Preparation of Compound 12e: In 6 mL solution of T3P in ethyl acetate,Compound 12d (150 mg, 0.39 mmol) and Compound 2a (156 mg, 059 mmol) werereacted at 100° C. for 1.5 hours in a pressured reactor. The mixture wascooled, diluted with water, and then extracted with ethyl acetate. Theorganic phases were combined, dried and concentrated, and separated bysilica gel plate to give 100 mg product.

Preparation of Compound I-101: In 1 mL DMA, Compound 12e (100 mg, 0.16mmol) and lithium chloride (35 mg, 0.83 mmol) were reacted at 100° C.for 3 hours. After the reaction finished, the mixture was diluted with10 mL water, and added with 2N hydrochloric acid to adjust pH to 5-6.The mixture was filtered, and the solid was dried under vacuum to give27 mg product. ¹HNMR (400 MHz, CDCl₃) δ: 7.72 (d, 1H, J=6.0 Hz), 7.30(m, 1H), 7.10-7.17 (m, 2H), 6.85-7.02 (m, 2H), 6.66-6.78 (m, 1H),6.38-6.51 (m, 1H), 6.19 (d, 1H, J=6.0 Hz), 5.09 (m, 1H), 4.74 (m, 1H),4.55 (m, 1H), 4.42 (m, 1H), 3.84-4.00 (m, 2H), 3.73 (m, 2H), 3.60 (m,2H), 3.40 (m, 2H), 2.88 (m, 1H), 1.84 (m, 1H), 1.52 (m, 2H); ESI-MS m/z(M+H)⁺ 537.2.

Embodiment 13: Preparation of Compound III-1

Preparation of Compound III-1: In 1 mL N,N-dimethylacetamide, CompoundII-5 (50 mg, 0.1 mmol), chloromethyl methyl carbonate (25 mg, 0.2 mmol),potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg, 0.02mmol) were reacted at 60° C. for 5 hours. TLC showed the reaction wascomplete, and the mixture was added with water to quench. 1Nhydrochloric acid was added to adjust pH to 3-4. The solid was filtered,dried, and separated by column chromatography to give 48 mg product.¹HNMR (400 MHz, DMSO-d6) δ: 7.37-7.44 (m, 2H), 7.13-7.18 (m, 2H), 7.10(m, 1H), 6.93 (m, 1H), 6.85 (t, 1H, J=7.6 Hz), 5.75 (m, 1H), 5.70 (m,1H), 5.66 (m, 2H), 5.43 (d, 1H, J=14.8 Hz), 4.43 (dd, 1H, J=2.4, 9.6Hz), 4.10 (dd, 1H, J=2.8, 10.8 Hz), 4.07 (d, 1H, J=14.4 Hz), 3.75 (d,1H, J=12.0 Hz), 3.72 (s, 3H), 3.44 (m, 1H), 3.02 (d, 1H, J=11.2 Hz),1.76 (m, 1H), 1.13 (m, 1H), 0.48 (m, 1H), 0.24 (m, 1H); ESI-MS m/z(M+H)⁺ 598.1.

Embodiment 14: Preparation of Compound III-2

Preparation of Compound III-2: In 1 mL N,N-dimethylacetamide, Compound11-6 (40 mg, 0.08 mmol), chloromethyl methyl carbonate (25 mg, 0.2mmol), potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg,0.02 mmol) were reacted at 60° C. for 5 hours. TLC showed the reactionwas complete, and the mixture was added with water to quench. 1Nhydrochloric acid was added to adjust pH to 3-4. The solid was filtered,dried, and separated by column chromatography to give 35 mg product.¹HNMR (400 MHz, DMSO-d6) δ: 7.40-7.42 (m, 2H), 7.25 (d, 1H, J=7.6 Hz),7.15 (m, 1H), 7.10 (m, 1H), 7.00 (d, 1H, J=7.2 Hz), 6.84 (t, 1H, J=7.6Hz), 5.75 (m, 4H), 5.43 (d, 1H, J=16.4 Hz), 4.57 (dd, 1H, J=3.2, 9.6Hz), 3.96-4.03 (m, 3H), 3.73 (s, 3H), 3.51 (t, 1H, J=10.0 Hz), 3.41 (s,1H), 0.75 (t, 2H, J=8.4 Hz), 0.50 (m, 2H); ESI-MS m/z (M+H)⁺ 598.1.

Embodiment 15: Preparation of Compound III-57

Preparation of Compound III-57: In 1 mL N,N-dimethylacetamide, Compound1-77 (49 mg, 0.1 mmol), chloromethyl methyl carbonate (25 mg, 0.2 mmol),potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg, 0.02mmol) were reacted at 60° C. for 5 hours. TLC showed the reaction wascomplete, and the mixture was added with water to quench. 1Nhydrochloric acid was added to adjust pH to 3-4. The solid was filtered,dried, and separated by column chromatography to give 43 mg product.¹HNMR (400 MHz, DMSO-d6) δ: 7.40 (m, 2H), 7.16 (m, 3H), 6.91 (m, 2H),5.83 (d, 1H, J=7.2 Hz), 5.74 (m, 1H), 5.57 (m, 1H), 5.44 (m, 1H), 5.29(s, 1H), 4.94 (d, 1H, J=13.6 Hz), 4.21 (d, 1H, J=14.4 Hz), 3.74 (s, 3H),2.45 (s, 1H), 2.05 (m, 4H), 1.93 (m, 2H); ESI-MS m/z (M+H)⁺582.1.

With the same way, the following compounds were synthesized:

Compound Structure LCMS ([M + H]⁺) Purity III-3

614.2 93% III-4

616.2 97% III-5

580.2 95% III-6

580.2 95% III-9

580.2 94% III-10

580.2 95% III-17

580.2 95% III-18

580.2 97% III-21

596.2 96% III-22

596.2 95% III-33

616.2 94% III-50

612.2 96% III-51

626.2 97% III-52

640.2 97% III-54

612.2 96% III-56

640.2 95% III-59

564.2 95% III-61

564.2 96% III-66

596.2 95% III-67

610.2 94% IV-1

604.2 93% IV-3

780.2 95% IV-9

620.5 93% IV-10

620.5 92% IV-11

796.2 96% IV-12

796.2 95%

Embodiment 16: In Vitro Bioactivity and Cytotoxicity Study

Test compounds: the compounds of the present disclosure: Compound I-1,Compound I-5, Compound I-7, Compound I-8, Compound I-9, Compound I-10,Compound I-14, Compound I-21, Compound I-65, Compound I-66, CompoundI-69, Compound I-77, Compound I-81, Compound I-83, Compound I-85,Compound I-89, Compound II-1, Compound II-2, Compound II-5, CompoundII-6, Compound II-7, Compound II-8, Compound II-9, Compound II-10,Compound II-13, Compound II-14, Compound II-17, Compound II-18, CompoundII-22, Compound II-29, Compound II-34, Compound II-65, Compound II-66,Compound II-67, Compound II-101; control compounds: VX-787, Baloxaviracid.

Test method for In vitro bioactivity study: MDCK cells were seeded into384-well cell cultrue plate at a density of 2,000 cells/well, and thenincubated at 37° C. overnight in a 5% CO₂ incubator. On the followingday, the compounds were diluted and added into the wells (3-folddilutions, 8 test concentrations), and the influenza virus A/PR/8/34(H1N1) strain was then added to the cell culture wells at 2*TCID90 perwell, and the final concentration of DMSO in the medium was 0.5%. Thecell plate was incubated at 37° C. for 5 days in the 5% CO₂ incubator.After 5 days of culture, the cell viability was measured using the cellviability detection kit CCK8. The raw data were subjected to nonlinearfitting analysis of the inhibition rate and cytotoxicity of thecompounds using GraphPad Prism software to obtain EC₅₀ values (see Table1 for the results).

Method for cytotoxicity study: The cytotoxicity assay and antiviralactivity assay of the compounds were performed in parallel, except forthe absence of virus, other experimental conditions were consistent withthe antiviral activity assay. After 5 days of culture, the cellviability was measured using the cell viability detection kit CCK8. Rawdata were used for calculating compound cytotoxicity (CC₅₀) (see Table 1for results).

TABLE 1 Cytotoxicity and inhibitory activity of compounds againstinfluenza virus A/PR/8/34 (H1N1) Results (nM) CPD ID EC₅₀ CC₅₀ I-10.50 >1000 I-5 0.44 >1000 I-7 0.83 >1000 I-8 0.75 >1000 I-9 0.40 >1000I-10 0.70 >1000 I-14 0.32 >1000 I-21 0.60 >1000 I-65 0.37 >1000 I-660.58 >1000 I-69 0.35 >1000 I-77 0.16 >1000 I-81 0.19 >1000 I-830.21 >1000 I-85 0.18 >1000 I-89 0.17 >1000 II-1 0.45 >1000 II-20.51 >1000 II-5 0.22 >1000 II-6 0.26 >1000 II-7 0.93 >1000 II-80.47 >1000 II-9 0.28 >1000 II-10 0.24 >1000 II-13 0.38 >1000 II-140.31 >1000 II-17 0.26 >1000 II-18 0.28 >1000 II-22 0.36 >1000 II-290.57 >1000 II-34 0.39 >1000 II-65 0.45 >1000 II-66 0.18 >1000 II-670.48 >1000 II-101 0.94 >1000 VX-787 1.4 >100 Baloxavir 1.4 >1000 acid

The results indicate that when compared with the control compounds, thecompounds of the present disclosure had superior activity against H1N1and had low cytotoxicity.

Embodiment 17: Rat PK Study

Intravenous injection: about 2 mg of Compound 11-5, Compound 11-6 andCompound 1-77 were accurately weighed out and added with appropriateamount of DMA, followed by vortex to a clean solution. An appropriatevolume of 30% Solutol HS-15 aqueous solution and saline were added andvortexed, so that DMA: 30% Solutol HS-15: saline was 20:20:60 (v/v/v).The solution was filtered to give a 0.05 mg·mL⁻¹ pharmaceuticalpreparation. SD rats were given a single injection of 0.25 mg·kg⁻¹ ofCompounds 11-5, 11-6 and 1-77 intravenously. 0.20 mL of blood wascollected from the jugular vein before administration and 0.083 h, 0.25h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after administration, andplaced in an EDTA-K₂ anticoagulation tube. 150 μL of whole blood wasaccurately pipetted immediately, and added into a test tube to which 450μL of acetonitrile has been added to precipitate proteins, and the tubewas vortexed, and placed on wet ice. It was stored in a −90˜−60° C.refrigerator for biological sample analysis. The concentration of thecorresponding compound in the plasma of S-D rats was determined byLC-MS/MS analysis. The corresponding pharmacokinetic parameters werecalculated using a non-compartmental model in Pharsight Phoenix 7.0. SeeTable 2a for the results.

Intragastric administration: about 4 mg of Compound III-2 was accuratelyweighed out and added with appropriate amount of PEG400, followed byvortex to a clean solution. An appropriate volume of 30% Solutol HS-15aqueous solution and saline were added, and followed by vortex to give apharmaceutical preparation of a concentration of 0.3 mg·mL⁻¹, withPEG400: 30% Solutol HS-15: saline=2:2:6 (v/v/v). SD rats were given asingle oral administration of 3.0 mg·kg⁻¹ of Compounds III-2, and theconcentration of Compound II-6 in the plasma of S-D rats was determinedbefore administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h and 24h after administration. See Table 2b for the results.

TABLE 2a PK Parameters (Intravenous Injection) of Test CompoundsCompound PK (i.v.) II-5 II-6 I-77 T_(1/2) (h) 2.49 2.97 2.96 AUC_(0-t)187 276 307 (ng · h · mL⁻¹) CL 20.9 13.6 13.0 (mL · kg⁻¹ · min⁻¹)Vd_(ss) 3.69 3.12 2.77 (L · kg⁻¹)

TABLE 2b PK Parameters (intragastric administration) of Test CompoundsCompound PK (i.g.) III-2 T_(1/2) (h) 3.32 T_(max) (h) 1.67 C_(max) 253(ng · mL⁻¹) AUC_(0-t) 1377 (ng · h · mL⁻¹) F (%) 47.2

The above results indicate that the compounds of the present disclosurehave a low clearance rate and a long half life. The compounds of thepresent disclosure are effective for being prodrug and have a highabsorption in vivo.

Embodiment 18: Efficacy on Mice

Female BALB/c mice were inoculated with influenza A virus (H1N1,A/WSN/33) by intranasal administration to establish an IAV mouseinfection model. The vehicle, Compound III-2 (15 mpk) or oseltamivirphosphate (15 mpk) were orally administered twice a day. Animal weightand survival status were monitored daily during the test, and on the 5thday, some animals were killed to take lung tissue for virus titerdetection, and the remaining mice were used for survival ratemonitoring. The in vivo anti-influenza virus efficacy of the testcompound was determined by virus titer in lung tissue, mouse body weightchange and survival rate.

Virus titer in lung tissue: On the 5th day after virus infection, theaverage virus titer in the lung tissue of mice in the vehicle controlgroup reached 7.20 Log 10 (number of plaques per gram of lung tissue),the average virus titer in the lung tissue of mice in the oseltamivirphosphate group was 3.74 Log 10 (number of plaques per gram of lungtissue). Compared with the vehicle group, oseltamivir phosphatesignificantly inhibited the replication of the virus in mice, and theaverage virus titer decreased by 3.46 Log 10 (number of plaques per gramof lung tissue), and the difference was very statistically significant(p<0.01) between the results, showing the expected efficacy; the averagevirus titer in the lung tissue of mice on the 5th day after treatmentwith test compound III-2 was 3.28 Log 10 (number of plaques per gram oflung tissue)), and compared with the vehicle group, the test compoundsignificantly inhibited the replication of the virus in mice, and theaverage virus titer decreased by 3.92 Log 10 (number of plaques per gramof lung tissue), and the difference was extremely statisticallysignificant (p<0.001) between the results, which is superior to thecontrol compound oseltamivir phosphate (Table 3).

TABLE 3 Virus Titer in Lung Tissue Statistical Influenza analysis VirusTiter (Compared Log10 with the (plaques solvent group) number/ MeanStatistic Group gram of lung) difference difference Solvent 7.20 ±0.1024 NA NA Oseltamivir 3.74 ± 0.5205 3.46 **(p < 0.01) phosphateCompound III-2 3.28 ± 0.2813 3.92 ***(p < 0.001) **P < 0.01 means verysignificant difference, P < 0.001 means extremely significant difference

Body weight change and result analysis: The mice in the vehicle controlgroup showed significant weight loss on the 3rd day after infection, andthen continued to decline or even die; the weight of the mice in theoseltamivir phosphate group and the Compound III-2 group remained stableduring the experiment, had no significant decline, and the mice were ingood health.

Survival rate and result analysis: the mice in the vehicle control groupwere found dead on the 7th day after infection, and on the 10th day, allmice died or were euthanized due to weight loss to the humanity endpoint, and the survival rate was 0%; the mice in the oseltamivirphosphate group and in the Compound III-2 group maintained healthyduring the experiment, and all animals survived to the predeterminedexperimental end point with a survival rate of 100%, indicatingexcellent anti-influenza efficacy in vivo.

The above description of the embodiments is merely to help understandingthe method and the core concept of the present disclosure. It should benoted that, for those ordinary skilled in the art, various improvementsand modifications can be made to the present disclosure without departfrom the technical principle of the present disclosure, and theseimprovements and modifications also fall within the protective scope ofthe present disclosure.

What is claimed is:
 1. A pyridone derivative represented by Formula (I)or a stereoisomer, a pharmaceutically acceptable salt, a solvatethereof,

wherein: (1) A is selected from N or CR₁, R₁ is selected from hydrogen,cyano, hydroxy, halogen, carboxyl, ester, amide, sulfonyl amide; or, R₁is selected from the following unsubstituted or substituted groups: C₁₋₆hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆hydrocarbylsulfydryl, carbonyl hydrazide, C₁₋₆ hydrocarbyl carbonyl,C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆ hydrocarbylcarbonyl amino, C₁₋₆hydrocarbyloxy carbonyl, C₁₋₆ hydrocarbylsulfinyl, C₁₋₆ hydrocarbylaminocarbonylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino,C₃₋₆ cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ cycloalkylaminocarbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆ cycloalkylaminocarbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈ heterocycloalkoxy, C₄₋₈heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylamino carbonyl, C₆₋₁₀aryl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxy hydrocarbyl, C₆₋₁₀ arylamino, C₆₋₁₀aryl sulfydryl, C₆₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆hydrocarbyl sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkylsulfonylamino, C₆₋₁₀ aryl sulfonyl, C₆₋₁₀ aryl sulfonylamino,aminooxalyl amino, aminooxalyl, C₆₋₁₀ arylamino carbonyl or C₅₋₁₀arylamino carbonylamino; (2) M is selected from N or CR₂, R₂ is selectedfrom hydrogen, cyano, hydroxy, halogen, carboxyl, ester, amide, sulfonylamide; or, R₂ is selected from the following unsubstituted orsubstituted groups: C₁₋₆ hydrocarbyl, C₁₋₆ hydrocarbyloxy, C₁₋₆hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl, carbonyl hydrazide, C₁₋₆hydrocarbyl carbonyl, C₁₋₆ hydrocarbylamino carbonyl, C₁₋₆hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl, C₁₋₆hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ cycloalkylaminocarbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆ cycloalkylaminocarbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈ heterocycloalkoxy, C₄₋₈heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylamino carbonyl, C₅₋₁₀aryl, C₅₋₁₀ aryloxy, C₅₋₁₀ aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀aryl sulfydryl, C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆hydrocarbyl sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkylsulfonylamino, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ aryl sulfonylamino,aminooxalyl amino, aminooxalyl, C₅₋₁₀ arylamino carbonyl or C₅₋₁₀arylamino carbonylamino; (3) Q is selected from N or CR₃, R₃ is selectedfrom hydrogen, cyano, carboxyl, ester, amide; or, R₃ is selected fromthe following unsubstituted or substituted groups: C₁₋₆ hydrocarbyl,C₃₋₆ cycloalkyl, C₄₋₈ heterocycloalkyl, C₅₋₁₀ aryl, C₃₋₆ cycloalkylsulfydryl, spirocyclic ring, bridged cyclic ring, C₃₋₆ cycloalkylsulfydryl C₁₋₆ hydrocarbyl, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbyl sulfydrylC₁₋₆ hydrocarbyl, C₃₋₆ cycloalkyl C₁₋₆ hydrocarbyl sulfydryl cycloalkyl,C₃₋₆ cycloalkyloxy cycloalkyl, cycloamide C₁₋₆ hydrocarbyl, cycloamidecycloalkyl, cyclosulfonyl C₁₋₆ hydrocarbyl, cyclosulfonyl cycloalkyl;(4) R₆ and R are connected and form a sixth ring together with anitrogen atom both connected therewith, and the sixth ring is spiro andoptionally contains 1, 2, 3 or more groups independently selected fromheteroatom, C═O, S═O or SO_(2,) in addition to the nitrogen atom which Rand R₆ are both connected with; a common carbon atom of the spiro ringand a nitrogen atom shared by the spiro ring and a parent ring areadjacent or spaced by one atom; a ring in the spiro ring that shares thenitrogen atom with a parent ring has an oxygen atom, or a nitrogen atomat a position opposite to the nitrogen atom; (5) m is 0, 1, 2, 3, 4 or5, and R₇ is selected from hydrogen, hydroxy, cyano, halogen, carboxyl,ester, sulfonyl amide, amide; or, R₇ is selected from the followingunsubstituted or substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl,carbonyl hydrazide, C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylaminocarbonyl, C₁₋₆ hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl,C₁₋₆ hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ cycloalkylaminocarbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆ cycloalkylaminocarbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈ heterocycloalkoxy, C₄₋₈heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylamino carbonyl, C₅₋₁₀aryl, C₅₋₁₀ aryloxy, C₅₋₁₀ aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀aryl sulfydryl, C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆hydrocarbylsulfonyl amide, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆cycloalkylsulfonyl amide, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ arylsulfonyl amide,aminooxalyl amino, aminooxalyl, C₅₋₁₀ arylamino carbonyl or C₅₋₁₀arylamino carbonylamino; (6) X is selected from Y(CH₂)_(n), —CH(OCH₃),—CH(SCH₃), N, O or S, Y is a single bond, NH, O or S, and n is 0, 1, 2or 3; (7) W is hydrogen or a group selected from the following groups:(a) —C(═O)—R₈; (b) —C(═O)—(CH₂)_(k)—R_(8,) k is selected from 0-3; (c)C(═O )—O —(CH₂)_(k)—R₈, k is selected from 0-3; (d) —CH₂—O—R₈; (e)—CH₂-O-C(═O)—R₈; (f) —CH₂—O—C(═O)—O—R₈; (g) —CH(—CH₃)—O—C(═O)—R₈; (h)CH(—CH₃)—O—C(C═O)—O —(CH₂)_(k)—R₈, k is selected from 0-3; (i)—CH₂—O—P(═O)(OH)₂; (j) —CH₂—O—P(═O)(OPh)(NHR₈); (k)—CH₂—O—P(═O)(OCH₂OC(═O)OR₈)₂; R₈ is selected from the followingunsubstituted or substituted groups: C₁₋₆ hydrocarbyl, C₁₋₆hydrocarbyloxy, C₁₋₆ hydrocarbylamino, C₁₋₆ hydrocarbylsulfydryl,carbonyl hydrazide, C₁₋₆ hydrocarbyl carbonyl, C₁₋₆ hydrocarbylaminocarbonyl, C₁₋₆ hydrocarbylcarbonyl amino, C₁₋₆ hydrocarbyloxy carbonyl,C₁₋₆ hydrocarbylsulfinyl, C₁₋₆ hydrocarbylamino carbonylamino, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₃₋₆cycloalkylsulfydryl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ cycloalkylaminocarbonyl, C₃₋₆ cycloalkylcarbonyl amino, C₃₋₆ cycloalkylaminocarbonylamino, C₄₋₈ heterocycloalkyl, C₄₋₈ heterocycloalkoxy, C₄₋₈heterocycloalkylamino, C₄₋₈ heterocycloalkyl sulfydryl, C₄₋₈heterocycloalkyl carbonyl, C₄₋₈ heterocycloalkylamino carbonyl, C₅₋₁₀aryl, C₅₋₁₀ aryloxy, C₅₋₁₀ aryloxy hydrocarbyl, C₅₋₁₀ arylamino, C₅₋₁₀aryl sulfydryl, C₅₋₁₀ aryl carbonyl, C₁₋₆ hydrocarbyl sulfonyl, C₁₋₆hydrocarbyl sulfonylamino, C₃₋₆ cycloalkyl sulfonyl, C₃₋₆ cycloalkylsulfonylamino, C₅₋₁₀ aryl sulfonyl, C₅₋₁₀ aryl sulfonylamino,aminooxalyl amino, aminooxalyl, C₅₋₁₀ arylamino carbonyl or C₅₋₁₀arylamino carbonylamino; (8) Ar₁ and Ar₂ are independently selected froma phenyl ring, or a heteroaromatic ring containing 1, 2, 3 or moreheteroatoms.
 2. The pyridone derivative or the stereoisomer, thepharmaceutically acceptable salt, or the solvate thereof according toclaim 1, wherein Ar₁ and Ar₂ are both a phenyl ring and the pyridonederivative is represented by Formula (II):

or, at least one of Ar₁ and Ar₂ is a heteroaromatic ring.
 3. Thepyridone derivative or the stereoisomer, the pharmaceutically acceptablesalt, or the solvate thereof according to claim 1, wherein, in theheterocyclic ring or the heteroaromatic ring, a heteroatom isdependently selected from N, O or S.
 4. The pyridone derivative or thestereoisomer, the pharmaceutically acceptable salt, or the solvatethereof according to claim 1, wherein the sixth ring is a spiro ring, aring in the spiro ring that shares the nitrogen atom with a parent ringis a 5-membered, 6-membered, 7-membered or 8-membered ring, and anotherring is a 3-membered, 4-membered, 5-membered or 6-membered carboatomic,oxygen-containing heterocyclic or sulfur-containing heterocyclic ringunsubstituted or substituted by a substituent selected from halogen,C₁₋₃ hydrocarbyl or C₁₋₃ halohydrocarbyl.
 5. The pyridone derivative orthe stereoisomer, the pharmaceutically acceptable salt, or the solvatethereof according to claim 4, wherein when the another ring has asubstituent, the substituent is selected from methyl, fluoro, chloro,bromo, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl,methoxymethyl, methoxyethyl, chloromethyl.
 6. The pyridone derivative orthe stereoisomer, the pharmaceutically acceptable salt, or the solvatethereof according to claim 1, wherein in Formula (I), the sixth ring isselected from the following groups:


7. The pyridone derivative or the stereoisomer, the pharmaceuticallyacceptable salt, or the solvate thereof according to claim 1, whereinthe pyridone derivative is represented by Formula IIa or Formula IIb:

in Formula IIa and Formula IIb, G is O; Z is selected from CH₂, O or S;p and q are respectively 0, 1 or 2, and the two are not 0 at the sametime, and when Z is O or S, p+q is greater than or equal to 2; and thedefinitions of W, R₇ and m are respectively the same as in claim
 1. 8.The pyridone derivative or the stereoisomer, the pharmaceuticallyacceptable salt, or the solvate thereof according to claim 7, wherein inFormula IIa and Formula IIb, p+q=1 or, 2 or 3, and Z is CH₂; or, p=1 or2, q=1 or 2, and Z is O or S.
 9. The pyridone derivative or thestereoisomer, the pharmaceutically acceptable salt, or the solvatethereof according to claim 7, wherein R₇ is selected from hydrogen,hydroxy, cyano, halogen, C₁₋₆ hydrocarbyl, C₁₋₆ halohydrocarbyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy C₁₋₆ hydrocarbyl, hydroxy C₁₋₆ hydrocarbyl, C₁₋₆hydrocarbyloxy.
 10. The pyridone derivative or the stereoisomer, thepharmaceutically acceptable salt, or the solvate thereof according toclaim 9, wherein R₇ is connected to a phenyl ring, R7 is selected fromF, CI, Br, methyl, or difluoromethyl; and m is 1, 2 or
 3. 11. Thepyridone derivative or the stereoisomer, the pharmaceutically acceptablesalt, or the solvate thereof according to claim 7, wherein W is selectedfrom the following groups: (a) —C(═O)—R₈; (b) —C(═O)—(CH₂)_(k)—R₈, k isselected from 0-3; (c) —C(═O)—O—(CH₂)_(k)—R₈, k is selected from 0-3;(e) —CH₂—O—C(═O)—R₈; (f) —CH₂—O—C(═O)—O—R₈; (g)—CH(—CH₃)—O—C(═O)_(k)—R₈; (h) —CH(—CH₃)—O—C(C═O)—O—(CH₂)_(k)—R₈, k isselected from 0-3; (i) —CH₂—O—P(═O)(OH)₂; (j) —CH₂—O—P(═O)(OPh)(NHR₈);(k) —CH₂—O—P(═O)(OCH₂OC(═O)OR₈)₂; R₈ is selected from methyl, ethyl,isopropyl, or butyl.
 12. The pyridone derivative or the stereoisomer,the pharmaceutically acceptable salt, or the solvate thereof accordingto claim 1, wherein the pyridone derivative is selected from thefollowing compounds:


13. A pharmaceutical composition containing the pyridone derivativerepresented by Formula (I) or the stereoisomer, the pharmaceuticallyacceptable salt, or the solvate thereof according to claim 1, whereinthe pharmaceutical composition is an antiviral pharmaceuticalcomposition optionally comprising one or more therapeutic agentsselected from the group consisting of a neuraminidase inhibitor, anucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor orother anti-influenza drugs.
 14. The pharmaceutical composition accordingto claim 13, wherein the pharmaceutical composition is a pharmaceuticalpreparation selected from a tablet, a powder, a capsule, a granule, anoral liquid, an injection, a suppository, a pill, a cream, a paste, agel, a pulvis, an inhalant, a suspension, a dry suspension, a patch, alotion or a nano preparation.
 15. A method for treating a viralinfection disease, wherein the method comprises administering to ananimal or human in need of the treatment an effective amount of thepyridone derivative represented by Formula (I) or the stereoisomer, thepharmaceutically acceptable salt, or the solvate thereof according toclaim 1, wherein the viral infection disease is an infectious diseasecaused by influenza type A and/or influenza type B.
 16. A method fortreating a viral infection disease, wherein the method comprisesadministering to an animal or human in need of the treatment aneffective amount of the pharmaceutical composition according to claim13, wherein the viral infection disease is an infectious disease causedby influenza type A and/or influenza type B.
 17. The pyridone derivativeor the stereoisomer, the pharmaceutically acceptable salt, or thesolvate thereof according to claim 9, wherein R₇ is connected to aphenyl ring and is selected from F, Cl, Br, methyl or trifluoromethyl;and m is 1 or 2.